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The effects of interferons on macrophages and their precursors
Veterinary Immunology and Immunopathology, 15 (1987) 129-165 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands
THE
EFFECTS
OF
INTERFERONS
ON
129
MACROPHAGES
AND
THEIR
PRECURSORS STEPHEN W. RUSSELL and JUDITH L . PACE Department of Comparative and Experimental Pathology College o f V e t e r i n a r y Medicine U n i v e r s i t y of F l o r i d a Gainesville, Florida, Supported,
in
32610 U . S . A .
part,
by
research
grants
CA
31199 and
CA
37187 from
the
National C a n c e r I n s t i t u t e . T A B L E OF CONTENTS 1.0
INTRODUCTION
2.0
GENERAL C O N S I D E R A T I O N S
3.0
GROWTH
AND
DIFFERENTIATION
EFFECTS
OF
INTERFERONS
ON
MONONUCLEAR PHAGOCYTES
4.0
3. I
Growth inhibitory effects.
3.2
Growth enhancing effects.
3.3
Differentiating effects.
INFLUENCE OF INTERFERONS ON THE
IMMUNOREGULATORY
ROLES OF
MONONUCLEAR PHAGOCYTES 4.1
Modulation of receptors and surface markers.
4.2
A n t i g e n p r e s e n t a t i o n a n d class [I MHC e x p r e s s i o n .
4.3
Interleukin I secretion.
4.4
Arachidonate
metabolism,
including
prostaglandin
and
leukotriene
s y n t h e s i s and s e c r e t i o n . 5.0
INFLUENCE
OF
INTERFERONS
ON
MONONUCLEAR
PHAGOCYTE
EFFECTOR FUNCTIONS 5.1
C h e m o t a x i s , Fc and C3 r e c e p t o r e x p r e s s i o n , a n d p h a g o c y t o s i s .
5.2
Activation for killing: 5.2.1
M a c r o p h a g e a c t i v a t i n g f a c t o r ( s ) and i n t e r f e r o n s .
5.2.2
Macrophage-mediated microbicidal activity.
5.2.3
Nonspecific killing of tumor cells.
5.2.4
M a i n t e n a n c e of a c t i v a t i o n f o r t u m o r cell k i l l i n g .
5.0
CONCLUSIONS
7.0
L I T E R A T U R E CITED
0165-2427/87/$03.50
© 1987 Elsevier Science Publishers B.V.
130
1.0
INTRODUCTION M a c r o p h a g e s a r e t h e most m a t u r e members o f t h e m o n o n u c l e a r p h a g o c y t e
differentiation regulatory and
series.
This
cell
type
has
a
wide
variety
of
effector
and
f u n c t i o n s t h a t a r e essential to h o s t d e f e n s e a g a i n s t m i c r o o r g a n i s m s
neoplasia.
secretion
of
Many
a
of
their
variety
of
capable in t h i s r e s p e c t t h a t , as much f o r t h e i r p o w e r f u l
protective
soluble
effects
products.
are
In
mediated
fact,
o v e r t h e last decade,
through
macrophages
the
are
so
t h e y h a v e become k n o w n
s e c r e t o r y c a p a c i t i e s as f o r t h e i r more t r a d i t i o n a l ,
phagocytic/scavenger role. M a n y o f the f u n c t i o n s o f m a c r o p h a g e s a r e m o d u l a t e d b y soluble m e d i a t o r s that
are
present
in
their
environment.
macrophages,
themselves;
products
of
T
interferon
is one of t h e most p o t e n t .
lymphocytes,
can be p r o d u c e d too,
can
however,
have
Many
so-called
T
these
are
lymphokines.
Of
The o t h e r i n t e r f e r o n s ,
b y a v a r i e t y o f cell t y p e s , important
of
produced
by
some o f t h e most i m p o r t a n t a r e s e c r e t o r y
regulatory
these,
gamma
alp~ha and b e t a ,
including macrophages. These,
influences.
Some
of
the
effects
that
i n t e r f e r o n s h a v e on m o n o n u c l e a r p h a g o c y t e s h a v e been r e v i e w e d in the r e c e n t p a s t (Basham and M e r i g a n , 1982; Vogel and F r i e d m a n , 1984). Precise
identification
of
the
diverse
i n t e r f e r o n s on macrophages has been d i f f i c u l t .
pharmacologic
actions
of
the
The p r i n c i p a l p r o b l e m has been
u n e q u i v o c a l a s s i g n m e n t of an a c t i v i t y to a g i v e n m e d i a t o r w i t h o u t c o n c e r n t h a t a c o n t a m i n a n t in t h e p r e p a r a t i o n c o u l d e i t h e r be p a r t l y o r w h o l l y r e s p o n s i b l e for the observed effect.
As a r e s u l t o f i m p r o v e d methods o f p u r i f i c a t i o n a n d ,
especially, the introduction
of r e c o m b i n a n t DNA t e c h n o l o g y , such w o r r i e s a r e
now m o s t l y a t h i n g o f the p a s t . T h e w a y s in which the i n t e r f e r o n s a f f e c t the biology
of
mononuclear
because of
this
fact
included
effects
antiviral
effects,
we r e q u i r e d
for
of
phagocytes
that
can now be e v a l u a t e d c r i t i c a l l y .
we u n d e r t o o k the w r i t i n g
interferons
on
mononuclear
that were described prior most t h a t
w e r e used in t h e s t u d i e s .
either
of this r e v i e w . phagocytes,
It
was
We h a v e
other
than
to mid 1986. In selecting p a p e r s
recombinant or highly purified
We r e g r e t if we i n a d v e r t e n t l y
interferons
overlooked anyone's
c o n t r i b u t i o n to t h i s r a p i d l y e x p a n d i n g b o d y o f k n o w l e d g e . 2.0
GENERAL C O N S I D E R A T I O N S T h e r e a r e s e v e r a l k e y c o n c e p t s o f a g e n e r a l n a t u r e t h a t a r e i m p o r t a n t to
understanding gamma
how
interferon
antiviral activity, interferon
will
the is
interferons
more
efficient
affect as a
mononuclear regulatory
t h a n e i t h e r alpha o r beta i n t e r f e r o n . continue
to
prove
more
effective
phagocytes.
molecule,
per
First, unit
of
Whether o r not gamma in
this
regard
when
r e g u l a t o r y a c t i v i t i e s a r e compared on a molar basis remains to be d e t e r m i n e d .
131
Second,
when
the
r e g u l a t o r y "effect
of a m i x t u r e of gamma i n t e r f e r o n
and
e i t h e r alpha o r beta i n t e r f e r o n is compared to t h a t of gamma used alone, the r e s u l t a n t effect is often more Ichan a d d i t i v e . T h i r d , gamma,
can
maintain
characteristics
of
the
expression
mononuclear
the i n t e r f e r o n s , especially
of ~ c e r t a i n
phagocytes
in
functions
the
presence
and
surface
of
negative
r e g u l a t o r y signals. T h e r e are many d i f f e r e n t s u b t y p e s of a l p h a ( l e u k o c y t e ) and at least two k i n d s of beta ( f i b r o b l a s t ) single
species
that
interferon.
is a n t i g e n i c a l l y
Gamma (immune) i n t e r f e r o n occurs as a distinct;
All o f
the i n t e r f e r o n s
interact
w i t h t h e i r t a r g e t cells t h r o u g h surface= r e c e p t o r s . Assuming t h a t t h e r e is l i t t l e difference
in
description
such
is
receptors
offered,
cell t y p e
based
to cell
principally
on
type, what
the f o l l o w i n g general is
known
about
these
s t r u c t u r e s on cells o t h e r than macrophages. It is g e n e r a l l y held t h a t a l p h a / b e t a i n t e f e r o n s share a common r e c e p t o r , while gamma i n t e r f e r o n i n t e r a c t s w i t h one t h a t is separate and d i s t i n c t . This fact is s u p p o r t e d by the r e s u l t s of competition studies ( A g u e t and B l a n c h a r d , 1981; Branca and Baglioni, Joshi et a l . , al.,
1982;
1981; Eppstein et a l . ,
K u s h n a r y o v et a l . ,
1985; Yonehara et a l . ,
1985; Finbloom et a l . ,
1985; Littman et a l . ,
1983; Zhang et a l . ,
1985;
1985; Merlin et
1986), by evidence t h a t the
b i n d i n g site f o r a l p h a / b e t a i n t e r f e r o n is the p r o d u c t of a d i f f e r e n t gene than the one f o r that
show
exposed Gupta,
gamma i n t e r f e r o n that
to
either
1984),
between (1982),
alpha/beta
the
alpha
( R a z i u d d i n et a l . ,
binding
or
beta,
sites but
are
not
receptors
in
when
gamma i n t e r f e r o n
and vice versa ( L i t t m a n et a l . , two
1984) and by e x p e r i m e n t s
internalized
cells
are
(Sarkar
and
1985). T h e r e may be o v e r l a p
some instances,
however.
Anderson
et
al.
f o r example, have shown t h a t human beta i n t e r f e r o n will compete w i t h
gamma i n t e r f e r o n to some e x t e n t f o r b i n d i n g to f i b r o b l a s t s , whereas alpha will not. (3elada et al. ( 1 9 8 4 ) ,
using mouse macrophages d e r i v e d from c u l t u r e s of
bone m a r r o w , have r e p o r t e d similar r e s u l t s , and Zhang et al.
as have Thompson et al.
(1986) u s i n g t h e human l y m p h o b l a s t o i d cell line,
(1985)
Daudi. In
the l a t t e r system, the b i n d i n g of beta could be blocked a p p r o x i m a t e l y 60% b y alpha
and
postulate interferon.
40% b y the In
gamma, causing
existence o f this
two
Thompson
receptors,
and
each of
his colleagues which
would
(1985) bind
to
beta
model, one r e c e p t o r would also b i n d gamma i n t e r f e r o n ,
while the o t h e r would a d d i t i o n a l l y recognize a l p h a . The number of r e c e p t o r s f o r e i t h e r a l p h a / b e t a o r gamma i n t e r f e r o n has g e n e r a l l y been estimated by Scatchard analysis to be f e w e r than 20,000 copies per cell, al.,
r e g a r d l e s s of the cell t y p e
1986; Celada et a l . ,
Langer et
al.,
( A g u e t and B l a n c h a r d ,
1984; Finbloom et a l . ,
1986; Littman et a l . ,
1981; A i y e r et
1985; Hannigan et a l . ,
1985; Merlin et a l . ,
1984;
1985; Weitzerbin et
132
al.,
1986).
The association constants
have r a n g e d from al.,
109M-1 to 1.2 x 108M-1 (Celada et al,
4 x
1985) while dissociation c o n s t a n t s ( K d )
10-11 to al,
(Ka) estimated from such b i n d i n g data
10-9M
1985;
1986;
( A g u e t and B l a n c h a r d ,
Hannigan
et a l . ,
Littman et a l . ,
198~;
1984; Finbloom et
have r a n g e d from a p p r o x i m a t e l y
1981; A i y e r et a l . ,
Kushnaryov
1985; Wietzerbin et a l . ,
et a l . ,
1986; Finbloom et
1985; L a n g e r et a l . ,
1986). C o n t r o v e r s y
still e x i s t s
as to w h e t h e r i n t e r f e r o n r e c e p t o r s e x i s t as homogeneous p o p u l a t i o n s . Of those who maintain t h a t t h e r e is h e t e r o g e n e i t y ( A i y e r et a l . , 1985; Hannigan et a l . ,
1984; O r c h a n s k y et a l . ,
1986; Finbloom et a l . ,
1986; Yonehara et a l . ,
1983),
some have s u g g e s t e d t h a t it is a h i g h a f f i n i t y species of r e c e p t o r t h a t is the b i o l o g i c a l l y r e l e v a n t one. The results of A i y e r et al. (1986) are of p a r t i c u l a r interest
in
the
macrophages
context
and
of
this
review
macrophage
( 5 0 0 / c e l l ) o f high a f f i n i t y
cell
because
lines.
the
They
work
was done using
reported
a
low
number
(Kd = 9.1 x 10-11M) r e c e p t o r s for gamma i n t e r f e r o n
and a l a r g e r number (4,400/ce11) of low a f f i n i t y b i n d i n g sites. Comparison of the r e c e p t o r a f f i n i t i e s and the c o n c e n t r a t i o n o f gamma i n t e r f e r o n needed to induce the e x p r e s s i o n of la and H2 a n t i g e n s led them to conclude that it is the h i g h a f f i n i t y
r e c e p t o r t h a t is b i o l o g i c a l l y r e l e v a n t . As few as 12 b i n d i n g
sites occupied on a steady
state basis were s u f f i c i e n t to cause i n d u c t i o n of
the e f f e c t . Both the N and C terminal p o r t i o n s of mouse gamma i n t e r f e r o n a p p e a r to be i m p o r t a n t f o r b i n d i n g to i t s r e c e p t o r (Russell, J. et a l . , al.
1986). S t r e u l i et
(1981) have also postulated t h a t human alpha i n t e r f e r o n has at least two
regions t h a t are of i m p o r t a n c e in b i n d i n g . The s t r u c t u r e s to which i n t e r f e r o n molecules b i n d on cell surfaces a p p e a r to be asymmetrical p o l y p e p t i d e s ( A g u e t and B l a n c h a r d , Gupta,
1984;
1981;
F a l t y n e k et a l . ,
Thompson
et
al.,
g l y c o p r o t e i n s (Joshi et a l . , Zhang
et
receptors
al.;
1986).
have
been
one
reported
exception
et
1982; L a n g e r et a l . , Wietzerbin
et
al.,
1982; S a r k a r and
al.,
1986)
et
al,,
Zhang
1985),
(Faltynek
1986; Raziuddin et a l . , 1986;
that
1984; Wietzerbin et a l . ,
(Thompson
to e x i s t as single e n t i t i e s
1983; Joshi et a l . , 1984;
Wietzerbin
1982; T r a u b et a l . ,
With
and
Gupta,
1983; Joshi et a l . ,
1985;
et a l . ,
are 1986; the
et a l . ,
1984; S a r k a r
1986)
t h a t have
a p p a r e n t molecular masses r a n g i n g between a p p r o x i m a t e l y 75 and 130 kDa. The r e c e p t o r s can e x i s t on cell surfaces in association w i t h coated pits {Kushnaryov internalized al.,
1984;
et a l . ,
1985;
( A g u e t and Kushnaryov
receptorlligand
complex
( S a r k a r and G u p t a ,
Zoon et a l . ,
Blanchard, et a l . , that
1984).
1981;
1985;
1983).
After
Zoon et a l . ,
is changed
the l i g a n d b i n d s it is
Branca et a l . , little
in
1982; Hannigan et
1983), a p p a r e n t l y as a size a f t e r
it is e n g u l f e d
Isolated nuclei a p p e a r to have r e c e p t o r s f o r beta
i n t e r f e r o n that are of h i g h e r a f f i n i t y
than those on the surface ( K u s h n a r y o v
133
et
al.,
1985).
This
observation
suggests
that
nuclear
binding
of
the
i n t e r f e r o n s may be necessary f o r them to induce t h e i r biological e f f e c t s . Work from
Isaiah F i d l e r ' s
also
suggests
laboratory
that
the
( F i d l e r et a l . ,
intracellular
1985; Saiki and F i d l e r ,
effects
of
interferon
may
1985)
be
most
i m p o r t a n t . Perhaps t h e i r most compelling data in s u p p o r t of this assertion is that
species r e s t r i c t i o n can be a b r o g a t e d i f the surface r e c e p t o r f o r gamma
interferon
is bypassed
( F i d l e r et a l . ,
1985): when the gamma i n t e r f e r o n s of
mouse and man were p r e s e n t e d in liposomes ( w h i c h are r e a d i l y phagocytosed by m a c r o p h a g e s ] , they were e q u a l l y e f f e c t i v e in a c t i v a t i n g the macrophages of either
species,
whereas t h e r e was s t r i c t s p e c i f i c i t y when cells were exposed
to gamma i n t e r f e r o n t h a t was free in the medium. These facts, t o g e t h e r w i t h intimations
from
Branca et a l . ,
other
kinds
of
experiments
1982; Wietzerbin et a l . ,
[Aguet
and
Blanchard,
1981;
1986), s u p p o r t a d e v e l o p i n g consensus
t h a t the i n t e r f e r o n s do not have to be d e g r a d e d a f t e r t h e y are i n t e r n a l i z e d to modulate cell f u n c t i o n . 3.0
GROWTH AND DIFFERENTIATION EFFECTS The i n t e r f e r o n s
regulates progenitor positive
a r e an i m p o r t a n t p a r t o f the n e t w o r k o f mediators t h a t
monocytopoiesis. cell and
in
the
The
bone
negative
mononuclear marrow
under
p h a g o c y t e series arises from a the
growth/differentiation
influence
stimuli,
of
The
a variety
of
differentiation
sequence in the marrow includes the f i r s t i d e n t i f i a b l e cell in this lineage, the monoblast, followed by the p r o m o n o c y t e and then the monocyte. The monocyte is the f i r s t
mononuclear p h a g o c y t e to leave the m a r r o w , so it is also found
n o r m a l l y in the b l o o d . The m a t u r e macrophage o r h i s t i o c y t e d e v e l o p s a f t e r the monocyte e x i t s the c i r c u l a t i o n and e n t e r s the tissues. Macrophages can d i f f e r strikingly
between
body
compartments.
They
are especially
"plastic"
cells,
w i t h many of t h e i r c h a r a c t e r i s t i c s and f u n c t i o n s d e t e r m i n e d by mediators t h a t a r e found in the tissue m i c r o e n v i r o n m e n t . The i n t e r f e r o n s can a f f e c t the g r o w t h of mononuclear phagocytes e i t h e r positively or negatively,
d e p e n d i n g on c o n d i t i o n s . The effects a r e seen e i t h e r
at the level of the p r o g e n i t o r cell in the bone marrow o r ,
to a much lesser
degree,
In a d d i t i o n ,
on
interferons
the can
p r o l i f e r a t i o n o f more d i f f e r e n t i a t e d cause
the
expression
of
forms.
characteristics
and f u n c t i o n s
the that
coincide w i t h the d i f f e r e n t i a t i o n of mononuclear p h a g o c y t e s . 3.1
G r o w t h I n h i b i t o r y Effects o f I n t e r f e r o n s At
the
growth
the level of the bone m a r r o w , the i n t e r f e r o n s n e g a t i v e l y a f f e c t of
a
wide
variety
of
hematopoietic
cell
types.
In
fact,
the
i n t e r f e r o n s may have an i m p o r t a n t role in the pathogenesis of some forms o f
134
aplastic
anemia
(Zoumbos
et
al.,
1985).
which
capacity
are
in
those
vitro
erythrocytes
to
that
yield
(Broxmeyer
limited differentiation
are
pluripotential
macrophages,
et
al.,
potential.
primary
targets
are
1982; Y a m a m o t o - Y a m a g u c h i et al.,
p r o g e n i t o r cells (Hale and M c C a r t h y , among
The
in
nature,
granulocytes,
1983),
as
well
as
i.e.,
early
1983),
with
the
megakaryocytes
those
that
have
or
more
Among t h e l a t t e r g r o u p a r e p r o g e n i t o r s w i t h
the c a p a c i t y to d e v e l o p i n t o e i t h e r macrophages and g r a n u l o c y t e s ( B r o x m e y e r et
al.,
1983;
Klimpel
Yamamoto-Yamaguchi
et
et
al.,
al.,
(Yamamoto-Yamaguchi
et
(Hale
1982) o r
and M c C a r t h y ,
deciding
factor
system.
When
is it
the has
al., kind
been
e f f e c t of t h e i n t e r f e r o n s the
other
1982;
1983)
or,
1983;
Hale
more
Moore and
erythrocytes
of
growth
examined
and
McCarthy,
selectively, Rouse,
macrophages
1983),
granulocytes
(Broxmeyer
stimulus
(Klimpel
that
et a l . ,
is used
et a l . ,
1982;
into
1982),
1983).
The
to d r i v e the
the
inhibitory
has been species specific (as is t h e case f o r most of
b i o l o g i c a l effects
of
the i n t e r f e r o n s ) .
The
inhibitory
p o t e n t i a l of
each of the i n t e r f e r o n s w o u l d , at f i r s t g l a n c e , a p p e a r to be equal ( R a e f s k y et al.,
1985).
However,
the
magnitude
of the effect
on p r o g e n i t o r s
probably
varies depending
on s e v e r a l c o n s i d e r a t i o n s ,
among w h i c h a r e t h e k i n d
and
concentration
colony
(CSF)
For
example,
of
stimulating
Yamamoto-Yamaguchi
containing
predominantly
inhibitory
on
(M-CSF)
compared
interferon
factor al.
(1983)
mouse alpha
progenitor
cells
to
granulocyte/macrophage
et
interferon
stimulated
those
growth
factor
are
employed. that
was more t h a n
with
which
that
ascertained macrophage
had
been
(GM-CSF).
a
mixture
20 times as
growth
factor
stimulated
The
degree
to
with which
is e f f e c t i v e as an i n h i b i t o r o f m a c r o p h a g e c o l o n y f o r m a t i o n a p p e a r s
to be r e l a t e d to the c o n c e n t r a t i o n of CSF t h a t is p r e s e n t in the e n v i r o n m e n t : i n c r e a s i n g t h e c o n c e n t r a t i o n of CSF overcomes t h e i n h i b i t o r y mouse (Klimpel et a l . ,
1982) o r human ( R a e f s k y et a l . ,
e f f e c t of e i t h e r
1985) i n t e r f e r o n s .
A
second v a r i a b l e t h a t i n f l u e n c e s i n h i b i t i o n is t h e t y p e of p r o g e n i t o r cell t h a t is targeted.
T h i s p o i n t was made c l e a r l y in a s t u d y o f human bone m a r r o w cells
conducted alpha,
by
beta
response
of
progenitor susceptible: beta
Broxmeyer and
on
al.
(1983).
interferons
pluripotential
and
Their
have
erythrocyte
results
equal
suggest
ability
progenitor
to
that
human
suppress
cells,
while
the the
t h a t g i v e s rise to g r a n u l o c y t e - m a c r o p h a g e colonies is d i f f e r e n t i a l l y gamma was the most e f f e c t i v e s u p p r e s s o r ,
interferon.
gamma
et
gamma
the
Klimpel et al.
(1983) a g r e e ,
granulocyte-macrophage
m i x t u r e of a l p h a / b e t a i n t e r f e r o n s .
then alpha and, lastly,
placing the inhibitory
progenitor
at
100
times
effect of that
of
a
The i n h i b i t o r y i n f l u e n c e o f a c o m b i n a t i o n o f
gamma and alpha i n t e r f e r o n s was i n c r e a s e d s y n e r g i s t i c a l l y o v e r t h e e f f e c t o f either
one
acting
alone
(Broxmeyer
et
al.,
1985;
Raefsky
et
al.,
1985).
135
A l t h o u g h the evidence was not c o n c l u s i v e , it a p p e a r e d from the r e s u l t s of cell depletion
studies
interferons
were
(Broxmeyer
et a l . ,
mediated d i r e c t l y ,
1983)
not
that
through
inhibitory the
effects
induction
of
the
of mediator
p r o d u c t i o n by mononuclear phagocytes a n d / o r l y m p h o c y t e s t h a t were r e s i d e n t in the bone m a r r o w . The specific mechanism of i n h i b i t i o n may be i r r e v e r s i b l e d o w n - r e g u l a t i o n of e x p r e s s i o n of surface r e c e p t o r s for CSF (Chen, 1986). In a d d i t i o n to p r o m o t i n g the p r o l i f e r a t i o n of bone marrow p r o g e n i t o r cells, at least some CSFs also induce the p r o d u c t i o n of a l p h a / b e t a i n t e r f e r o n s and
prostaglandins
mononuclear
that
phagocytes.
have The
a d h e r e n t bone marrow cells
the
capacity
producers
to
decrease
of these i n h i b i t o r y
(Moore et a l . ,
proliferative
potential
that
was
caused
by
198qb). The r e d u c t i o n
interferon
produced
macrophages was l i k e l y a consequence of induced d i f f e r e n t i a t i o n , i n h i b i t i o n of p r o l i f e r a t i o n alpha/beta being
interferons,
(Moore et a l . ,
prostaglandin
1985).
E (PGE)
Concern
that
in
the
mouse,
by
showing t h a t
obtained
when
C3H/HeJ
mice were exposed
adherent
bone to
by
not d i r e c t
p r o d u c t i o n of
o r all of these mediators was
induced by c o n t a m i n a t i n g e n d o t o x i n , and not by CSF,
least
of
198qa,b), and the effect of each
a p p e a r e d to be mediated i n d e p e n d e n t l y (Moore et a l . , in
production
mediators were
was a l l a y e d , at
similar levels of p r o d u c t i o n could be
marrow CSF.
cells
of
Further,
endotoxin-hyporesponsive, a highly
specific a n t i s e r u m
a g a i n s t CSF also a b r o g a t e d p r o d u c t i o n of both i n t e r f e r o n and PGE (Moore et a l . , 198qb). In a d d i t i o n
to i n t e r f e r i n g
with
the response of p r o g e n i t o r cells in
the m a r r o w , the i n t e r f e r o n s also have a n t i p r o l i f e r a t i v e effects on mononuclear p h a g o c y t e cell lines, e i t h e r the human line, U937 ( H a t t o r i et a l . , et a l . ,
1983) o r the mouse line, J77q.2 {Nagata et a l . ,
1983; Ralph
1984; Schneck et a l . ,
1982). The i n t e r f e r o n used in the s t u d y of U937 was gamma, while i n h i b i t i o n of
proliferation
interferons.
of
J774.2
was
induced
by
a
mixture
of alpha
and
beta
In the l a t t e r case the i n h i b i t o r y e f f e c t was shown by genetic and
biochemical means to be cyclic A M P - d e p e n d e n t . 3.2
G r o w t h Enhancing Effects of the I n t e r f e r o n s While
inhibitory
the
effects,
mononuclear
interferons they
phagocytes
can if
are also
perhaps
best
enhance
the
conditions
are
known
for
proliferative
appropriate.
For
their
growth
capacity
example,
of
when
mouse bone marrow cells were i n c u b a t e d w i t h low c o n c e n t r a t i o n s of a l p h a / b e t a i n t e r f e r o n s , the p r o d u c t i o n of macrophage colonies in response to GM-CSF was s i g n i f i c a n t l y increased, w h i l e the n u m b e r o f colonies p r o d u c e d by M-CSF was inhibited
(Yamamoto-Yamaguchi et
al.,
1983).
Similarly,
response
to
CSF
d e r i v e d from p r e g n a n t mouse u t e r u s was augmented by a m i x t u r e of alpha and
136
beta
interferons,
w h i l e t h e c o m b i n a t i o n o f these same i n t e r f e r o n s
from e n d o t o x i n - s h o c k e d l u n g was i n h i b i t o r y
(Hale and M c C a r t h y ,
with
CSF
1982). Moore
and Rouse (1983) f o u n d t h a t p r e t r e a t m e n t o f mouse m a r r o w w i t h a m i x t u r e o f alpha
and
beta
interferons
caused
macrophage
progenitors
to
retain
their
r e s p o n s i v e n e s s to low c o n c e n t r a t i o n s o f m a c r o p h a g e CSF, w i t h t h e r e s u l t t h a t more
colonies
were
produced
than
without
pretreatment.
Enhancement
was
c l e a r l y d u e to t h e p r o l i f e r a t i o n o f an i n c r e a s e d n u m b e r o f p r o g e n i t o r s and not to a u g m e n t e d p r o l i f e r a t i o n o f the same n u m b e r o f c o l o n y - f o r m i n g cells.
Since
CSF can cause t h e s e c r e t i o n o f i n t e r f e r o n b y cells in t h e bone m a r r o w , Moore and Rouse s p e c u l a t e d t h a t t h e m a g n i t u d e of t h e i n t e r f e r o n marrow dictates interferon)
whether
or inhibited
m o n o c y t o p o i e s i s is a u g m e n t e d (high concentration).
production
in the
(low c o n c e n t r a t i o n o f
These data c o l l e c t i v e l y s u p p o r t
t h e c o n c e p t t h a t t h e c o n c e n t r a t i o n o f i n t e r f e r o n and t h e k i n d of CSF a r e b o t h i m p o r t a n t i f an a u g m e n t e a g r o w t h response o f m a c r o p h a g e p r o g e n i t o r s is to be seen. As an i m p o r t a n t p r a c t i c a l p o i n t ,
the results of
also
of
be
influenced
interferon liquid
and
culture
by
the
GM-CSF but
conditions
stimulated
inhibited
(Yamamoto-Yamaguchi et al., 3.3
the
colony
culture:
formation formation
such e x p e r i m e n t s could
a mixture of
of
in
semisolid
agar
Differentiatinc~ Effects of t h e I n t e r f e r o n s Interferon
1983a).
metamyelocytes
gamma,
but
not
Surprisingly, or
bands
alpha
or
neutrophilic
could
also
undergo monocytic differentiation. Similarly;
gamma
was
the
monocytoid differentiation et a l . ,
culture
1983}.
beta,
caused human c h r o n i c
m y e l o g e n o u s leukemia cells to d i f f e r e n t i a t e to m o n o c y t e - l i k e cells al.,
alpha/beta
m a c r o p h a g e colonies in
be
granulocytes induced
by
as
gamma
mature
as
interferon
to
T h e r e was no e f f e c t on m a t u r e n e u t r o p h i l s .
only
interferon
that
would
cause
in t h e m y e l o m o n o c y t i c human cell l i n e ,
1984; K o e f f l e r et a l . ,
(Perussia et
significant H L - 6 0 (Ball
1984). In a s e p a r a t e i n v e s t i g a t i o n , H a t t o r i et al.
(1983) saw no e v i d e n c e o f d i f f e r e n t i a t i o n o f H L - 6 0 e x p o s e d e i t h e r to alpha o r beta
interferons;
they
did
not
assess
the
effects
of
gamma.
These
same
a u t h o r s d i d see i n d u c t i o n o f m o n o c y t o i d d i f f e r e n t i a t i o n in t h e human cell l i n e , U937,
w h e n i t was e x p o s e d to e i t h e r a l p h a o r beta i n t e r f e r o n .
normal human m o n o c y t e s b y expression
of
morphologic
Becker
(cell v o l u m e ) ,
leucine aminopeptidase) and
functional
i n c r e a s e as m o n o c y t e s m a t u r e . (1985),
working
endogenously by
with
mice,
alpha
In s t u d i e s o f
i n t e r f e r o n d e c r e a s e d the
enzymatic
(phagocytosis)
(acid
phosphatase
markers
that
and
normally
Gamma i n t e r f e r o n also was shown to decrease
the development of phagocytic activity al.
(1984a),
(Becker,
1984b). In c o n t r a s t , Moore et
showed t h a t a l p h a / b e t a i n t e r f e r o n s
mouse bone m a r r o w cells p o s i t i v e l y a f f e c t e d
maturation (phagocytic capability) of progeny macrophages.
produced
the functional
137
4.0
INFLUENCE
OF
INTERFERONS
ON THE IMMUNOREGULATORY
ROLE OF
MACROPHAGES 4. I
M o d u l a t i o n o f R e c e p t o r s and S u r f a c e M a r k e r s The
interferons
affect
the
m a r k e r s on m o n o n u c l e a r p h a g o c y t e s
expression
(Table
I).
of
will summarize w h a t is k n o w n a b o u t these c h a n g e s , class
receptors
and
surface
The r e m a i n d e r o f t h i s section with the exception of the
II MHC a n t i g e n s t h a t a r e c o v e r e d in section 4.2, and t h e r e c e p t o r s t h a t
a r e associated w i t h p h a g o c y t o s i s (Fc and C3; see section 5 . 1 ) . 4.1.1
Fc R e c e p t o r s f o r IgM and 19E The
opsonized with
IgM,
receptor
that
Fc
1969; M a n t o v a n i ,
m a c r o p h a g e s had
least one of t h e
the
portion
interferons
an immune r e s p o n s e .
This
of view,
the
namely,
indicator
IgM
binds
particles
1981). Beta i n t e r f e r o n increased t h e
to b i n d
enhances
IgM (Vogel et a l . , the ability
bind particles that are opsonized with the first
the
of
b u t does n o t n e c e s s a r i l y p r o v i d e t h e signal f o r i n g e s t i o n
( L a y and N u s s e n z w e i g , capacity
for
in
particles
that
1983a). T h u s ,
at
macrophages h a v e to
a n t i b o d y t h a t is p r o d u c e d in
fact is also i m p o r t a n t from a p u r e l y technical p o i n t interpretation
o f complement b i n d i n g
are opsonized with
studies where
IgM and c o m p l e m e n t .
If t h e
IgM
used to f i x complement b i n d s to Fc r e c e p t o r s , t h e n it c a n n o t be d i s t i n g u i s h e d w h e t h e r it is t h e a n t i b o d y o r t h e complement t h a t is r e s p o n s i b l e f o r b i n d i n g ( V o g e l et a l . ,
1983a).
Spiegelberg,
1981)
The cell
to secrete
1982). U937
receptor
human
macrophages
(Anderson
and
because its e n g a g e m e n t induces the
mediators
(Rankin
gamma
interferon
et a l . ,
1982;
R o u z e r et a l . ,
significantly
increased
the
of t h i s r e c e p t o r on t h e s u r f a c e o f t h e human m o n o c y t i c cell l i n e ,
(Naray-Fejes-Toth
homogeneous
by
and
Scatchard
dissociation constant
(Kd).
interferon
same
had
the
Guyre,
is n o t y e t k n o w n ; the
1984).
analysis, As
and
The
receptors
there
was
is so o f t e n t h e case,
magnitude
biological relevance of up-regulation increase
on
important one,
inflammatory
Recombinant
expression
IgE
is an
of
effect
as
no
induced
change
in
were their
n e i t h e r alpha n o r beta gamma
interferon.
The
o f t h e Fc r e c e p t o r f o r IgE b y i n t e r f e r o n
h o w e v e r , one c o u l d s p e c u l a t e t h a t t h i s may be a means to
availability
of
inflammatory
mediators
in
the
locale
of
an
IgE-mediated allergic reaction. 4.1.2
Interleukin 2 (IL-2) receptor Gamma
express
interferon
also
receptors for the lymphokine,
t h e p e r i p h e r a l blood ( H e r r m a n n et a l . ,
induces interleukin
mononuclear
phagocytes
to
2. N e i t h e r m o n o c y t e s from
1985; H o l t e r et a l . ,
1986) n o r cells o f
138
TABLE I Effects of i n t e r f e r o n s on t h e e x p r e s s i o n of s u r f a c e m a r k e r s and r e c e p t o r s on m o n o n u c l e a r p h a g o c y t e s
Receptor or marker
R e g u l a t o r y e f f e c t o f IFN Alpha Beta Gamma
Selected references
Da
B e c k e r et a l . , 1983; E s p a r z a , et a l . , 1986
NK
?
Esparza et a l . , 1986; W r i g h t et a l . , 1986
NK
D
NK
FcR IgG I
U
U
U
Vogel et a l . , 1983a,b; Y o s h i e et a l . , 1982
FcR IgG II
U
U
U
Vogel et a l . , 1983b; Y o s h i e et a l . , 1982
FcR IgM
NK
U
NK
FcR IgE
u
u
U
N a r a y - F e j e s - T o t h and G u y r e , 1984
Class I MHC
U
U
U
K e l l e y et a l . , Wong et a l . , 1984
Class II MHC
?
?
U
B e c k e t , 1984b; K e l l e y et a l . , 1984; Rhodes et a l . , 1983; Sztein et a l . , 1984
NK
NK
D
Hamilton et a l . ,
O
O
U
H e r r m a n n et a l . , 19851 H o l t e r et a l . , 1986
NK
NK
U
K o e s t l e r et a l . ,
Mannosyl, fucosyl terminated g l y c o p r o t e i n s
D
NK
D
Mokoena & G o r d o n , 1985
Lymphocyte function antigen 1 (LFA-I)
O
O
U
S t r a s s m a n n , et a l . , 1985
CR I (C3b)
D
O
CR 3 (C3bi)
NK
Mac-1 ( C 3 b i )
Transferrin Interleukin 2 (IL-2; Tac s u r f a c e a n t i g e n ) A n t i g e n 158.2
Vogel et a l . ,
Vogel e t a l . ,
1983a
1983a
1984; 1983,
a U = s t r o n g l y up r e g u l a t e d ; u = s l i g h t l y up r e g u l a t e d ; D = d o w n r e g u l a t e d ; O = no e f f e c t ; ? = i n c o n s i s t e n t r e s u l t s ; a n d NK = n o t k n o w n .
1984
1985
139
the human monocytic line, U937, o r myelomonocytic line, HL-60 ( H e r r m a n n et
al.,
1985) e x p r e s s IL-2 r e c e p t o r s c o n s t i t u t i v e l y . E x p o s u r e of fresh monocytes
to c u l t u r e c o n d i t i o n s caused a p p r o x i m a t e l y a t h i r d of the population to become positive,
w i t h gamma i n t e r f e r o n causing double t h a t p e r c e n t a g e to e x p r e s s the
receptor
at
monoclonal
twice
the
antibody
number
followed
per by
cell.
Immunoprecipitation
SDS-PAGE
analysis
r e c e p t o r induced on monocytes ( H o l t e r et a l . , al., B
1985) is s t r u c t u r a l l y lymphocytes.
antibody
anti-Tac,
that
2A3),
to
indication
binding
also
bound
anti-Tat that
the
1986) and U937 ( H e r r m a n n et
similar to the one t h a t is found on a c t i v a t e d T and
Further
additional
with
suggested
recognize the
that
studies: the
receptor
it is the same r e c e p t o r comes from
two
IL-2
monoclonal a n t i b o d i e s o t h e r
r e c e p t o r of l y m p h o c y t e s
expressed
by
monocytes.
than
(Tu69 and
Cycloheximide
p r e v e n t e d e x p r e s s i o n of the r e c e p t o r by monocytes stimulated w i t h i n t e r f e r o n , s u g g e s t i n g t h a t de novo s y n t h e s i s is i n v o l v e d r a t h e r than the unmasking of cryptic
r e c e p t o r s . N e i t h e r o f the two g r o u p s r e p o r t i n g this phenomenon found
significantly
increased DNA s y n t h e s i s
stimulated in gamma i n t e r f e r o n - t r e a t e d
mononuclear phagocytes t h a t were exposed to I L - 2 . T h u s ,
it is l i k e l y t h a t the
IL-2 r e c e p t o r is not i n v o l v e d in g r o w t h r e g u l a t i o n of mononuclear p h a g o c y t e s , as it is in l y m p h o c y t e s . Whether engagement of the r e c e p t o r will u l t i m a t e l y be shown to i n f l u e n c e d i f f e r e n t i a t i o n , a f f e c t m a c r o p h a g e / l y m p h o c y t e i n t e r a c t i o n s , o r have some o t h e r i m m u n o r e g u l a t o r y e f f e c t remains to be seen. 4.1.3
T r a n s f e r r i n and mannosyl, fucosyl r e c e p t o r s Macrophages
addition
to
contain,
they
processing
macrophages
also to
effete
have
gamma
(Hamilton et a l . ,
have an
a
integral
erythrocytes surface
interferon
role
and
in
the
iron
metabolism.
hemoglobin
receptor
for
transferrin.
reduced
expression
of
that
they
Exposure this
In of
receptor
1984), a phenomenon t h a t could be mimicked w i t h e i t h e r the
calcium i o n o p h o r e , A23187, o r p h o r b o l m y r i s t a t e acetate (Weiel et a l . , Loss of r e c e p t o r s ,
not decreased a f f i n i t y ,
b i n d i n g of t r a n s f e r r i n .
1985).
was r e s p o n s i b l e f o r the diminished
The p h y s i o l o g i c a l relevance of this o b s e r v a t i o n is, as
yet, unknown. Another lectin-like; fucose
This
monocytes f r e s h l y Exposure
receptor
of
this
is
on
expressed
isolated from the b l o o d , of
the
lymphocytes or interferon expression
receptor
mononuclear
phagocytes
is
i t b i n d s g l y c o p r o t e i n s t h a t are t e r m i n a t e d by e i t h e r mannose o r
residues.
culture.
surface
cells
either
to
to a s l i g h t
d e g r e e by
human
b u t increases w i t h time spent in specifically
challenged,
immune
( e i t h e r alpha o r gamma) r e v e r s i b l y d o w n - r e g u l a t e d
receptor
in
culture
(Mokoena
and
Gordon,
1985).
The
e f f e c t could be p r e v e n t e d by the a n t i i n f l a m m a t o r y s t e r o i d , dexamethasone. In
140
c o n t r a s t to w h a t is g e n e r a l l y f o u n d , any,
in this human system t h e r e was l i t t l e , if
d i f f e r e n c e between the effects of alpha and gamma i n t e r f e r o n s .
other
hand,
only
gamma i n t e r f e r o n
On the
had the c a p a c i t y to d o w n - r e g u l a t e this
r e c e p t o r on mouse macrophages. 4.1.4
L y m p h o c y t e f u n c t i o n anti~len 1 and antic=len 158.2 These
(Strassmann
et
quiescent,
al.,
antigens 1985,
peritoneal
(inflammatory) that
stimulated
LFA-1 by
macrophages
marked
activating
thioglycollate, exposing
but
them
either
stimulate e x p r e s s i o n . However, one
must
interferons
lack
activity,
They
then
In
kinds
of
i.e., elicited
were e i t h e r
vitro,
LFA-1
Thus,
it would
partially or
could
be
fully
induced
on
e l i c i t e d p e r i t o n e a l macrophages by or
bacterial
lipopolysaccharide.
at the c o n c e n t r a t i o n s used, were able to
judgment
because by
Some
LFA-1
resident,
in view of the a b i l i t y t h a t LPS had to induce
reserve
phagocytes
markers.
by
b u t macrophages t h a t were e i t h e r
gamma i n t e r f e r o n
expression,
macrophages.
mice.
macrophages t h a t
agents.
as
expressed
e x p r e s s e d the a n t i g e n .
not proteose p e p t o n e ,
to
primarily
not of
killing
N e i t h e r alpha n o r beta i n t e r f e r o n s ,
mononuclear
used is
macrophages were p o s i t i v e ,
primed or fully activated for appear
are
1986)
as
LPS
stimulating
to
whether
mediates
many
secretion
of
or
not
alpha/beta
of
its
effects
on
interferons
by
these
feed back on the cells t h a t p r o d u c e d
them in an
a u t o c r i n e manner. A d d i t i o n a l studies are needed w i t h h i g h e r c o n c e n t r a t i o n s of exogenous alpha and beta i n t e r f e r o n s to e n s u r e t h a t they are not simply less e f f i c i e n t than gamma at i n d u c i n g e x p r e s s i o n of L F A - 1 . The e x p r e s s i o n of a n t i g e n also
up-regulated
macrophages t h a t
by
gamma
158.2
interferon.
were primed for
( K o e s t l e r et a l . ,
Its
expression
t u m o r cell k i l l i n g ,
i.e.,
1985)
increased
is on
changed to the
e x t e n t that they could be t r i g g e r e d to develop c y t o l y t i c a c t i v i t y by v e r y small amounts of a second, t r i g g e r i n g that
they
were
tumoricidal.
signal (such as LPS),
Treated
ingested L i s t e r i a monocyto~enes.
cells
b u t not to the e x t e n t
were m i c r o b i c i d a l ,
Like L F A - 1 ,
however,
for
the e x p r e s s i o n of this antigen
was also increased a f t e r macrophages were exposed to LPS, b u t not to e i t h e r alpha
or
beta
interferons.
Caution
is
needed
again
here,
however,
in
i n t e r p r e t i n g r e s u l t s , as the c o n c e n t r a t i o n of a l p h a / b e t a i n t e r f e r o n s used was only
100 times t h a t of gamma (based on a n t i v i r a l u n i t s ) .
500 to
1,000 times more alpha
or
beta
interferon
i m m u n o r e g u l a t o r y potential of gamma i n t e r f e r o n .
In many instances,
is needed
to mimic the
141
4.2
Anticjen Presentation and Class II MHC Expression For
efficient
development of
immune responses,
antigen
p r e s e n t e d to l y m p h o c y t e s b y a n t i g e n p r e s e n t i n g cells ( A P C } , class
II MHC gene p r o d u c t s .
class
II
antigens
positioned
at
C e r t a i n APC,
constitutively.
portals
of
entry,
be
such as d e n d r i t i c cells, e x p r e s s
Generally,
antigen
must
in c o n c e r t w i t h
such
are
cells
sessile,
are
and
relatively they
are
few, poorly
p h a g o c y t i c . Mononuclear p h a g o c y t e s g e n e r a l l y do not e x p r e s s class II a n t i g e n s unless t h e y
have been a p p r o p r i a t e l y
stimulated to do so. They c o n s t i t u t e a
h i g h l y mobile pool o f a v i d l y p h a g o c y t i c cells t h a t can be marshalled r a p i d l y at a site.
Thus,
one m i g h t view mononuclear phagocytes as a r e s e r v e that is
mobilized to augment and APC
a m p l i f y immune responses which a r e i n i t i a t e d by
r e s i d e n t at a site of a n t i g e n i n c u r s i o n .
phagocytes
provide
ability
process,
to
increased i.e.,
p a r t i c u l a t e material t h a t value,
however,
numbers
ingest,
of
the
cells
cells,
degrade
they encounter.
unless
Not only do these mononuclear they
and
also c o n t r i b u t e
present
to
the
lymphocytes
Such a r e s e r v e would be of l i t t l e
that
constitute
it
could
be i n d u c e d
to
e x p r e s s class II a n t i g e n s . From the many c i t a t i o n s t h a t that
gamma i n t e r f e r o n
mononuclear number
cells
expression Papiernik
per et
After
expressing cell
al.,
the conclusion is inescapable
induces the e x p r e s s i o n of class
phagocytes.
of
follow,
were
class
II
increased
1986).
1,25-dihydroxyvitamin
exposure
(Becker,
et
gamma
antigens
Expression
D 3 (Morel
to
was
al.,
and
II MHC a n t i g e n s on interferon,
the
1985;
Cershon
enhanced
1986).
density
by
While
et
the
both
the
of a n t i g e n al.,
1985;
presence
most w o r k e r s
of
would
s u p p o r t the notion of a d i r e c t e f f e c t b y gamma i n t e r f e r o n on its t a r g e t cells, there
is one r e p o r t (Walker et a l . ,
1984) o f gamma i n t e r f e r o n also a c t i n g to
e l i c i t the release of a class I I - i n d u c i n g f a c t o r t h a t n e i t h e r induces a n t i v i r a l activity
nor
blocks
the
class
II-inducing
effects
of
gamma
interferon.
Messenger RNA specific for class II p o l y p e p t i d e s could be d e m o n s t r a t e d in the cells of mononuclear p h a g o c y t e lines of both human b e i n g s (HL-60; K o e f f l e r et al.,
1984)
and mice (P388D1;
treated
with
gamma
adults,
fetal
(Kelley et a l . ,
monocytes
would
also
mononuclear
phagocytes
antigens
culture
in
Sztein
et
al.,
In
addition
1984) a f t e r
they
mononuclear
to gamma i n t e r f e r o n
by
had been
phagocytes
of
1984) human
d e v e l o p i n g class
II
A similar effect could be o b s e r v e d when p u r i f i e d
were allowed
and
to
1984) and neonatal (Stiehm et a l . ,
respond
a n t i g e n s on t h e i r s u r f a c e s .
1984;
Nakamura et a l . ,
interferon.
were
1984).
then Such
antigen presenting capabilities with
to
lose t h e i r
treated cultured
complement of
w i t h gamma i n t e r f e r o n cells
concomitantly
class
II
(Belier,
reacquired
new class II a n t i g e n e x p r e s s i o n ( B e l i e r ,
198q}. I m p l i c i t in the r e s u l t s o f these l a t t e r s t u d i e s , and those of Steeg et al.
142
(1982b),
is
the
fact
phagocytes cannot
that
expression
of class
be maintained w i t h o u t
II
antigen
continuous
by
mononuclear
stimulation by
gamma,
and p e r h a p s o t h e r k i n d s of i n t e r f e r o n . Whether expression
or
o f class
not
alpha
and
beta
interferons
also
induce
q u e s t i o n . T h e r e are clear r e p o r t s of t h e i r ineffectiveness (Ball et a l . , Becket, 1984;
1984b; Kelley et a l . , Vogel
et
unequivocal 1983;
al.,
class
1984; P a p i e r n i k et a l . ,
1983a);
however,
I I-inducing
Sztein et a l . ,
different
1984).
inductive
activity
applicable
efficiencies,
potentials
was
for
reduced,
alpha
and
at
least
to alpha
rather
1984;
1986; V i r e l i z i e r et a l . , two
studies
interferon
The a p p a r e n t d i s c r e p a n c y
the a l p h a / b e t a and gamma i n t e r f e r o n s . is
the
II a n t i g e n s on mononuclear phagocytes is still an open
do
ascribe
(Rhodes
et
al.,
may again be due to
than an absolute d i f f e r e n c e
between
The likelihood t h a t such an a r g u m e n t
however,
by
the
gamma i n t e r f e r o n s
finding
of
similar
inductive
when the two i n t e r f e r o n s
were
d i r e c t l y compared in the same series of e x p e r i m e n t s (Sztein et a l . , 1984). Numerous
agents
will
interfere
with
the
capacity
of
gamma
i n t e r f e r o n to induce class II a n t i g e n e x p r e s s i o n . An a p p a r e n t p a r a d o x is the fact
that,
antigens
while (Rhodes
alpha/beta et a l . ,
interferons
1983;
caused
Sztein et a l . ,
the
expression
1984),
they
of class
interferon~s a b i l i t y to induce these surface a n t i g e n s ( l n a b a et a l . , et a l . ,
inhibitors
et
al.,
antibody Vogel,
1986; Ling
1985). Such i n h i b i t i o n was a p p a r e n t l y not mediated by p r o s t a g l a n d i n s ,
because (Ling
II
i n h i b i t e d gamma
of
the
1985).
specific
cyclooxygenase
Instead,
for
the
alpha/beta
synthetic
inhibitory
interferons.
pathway
effect
could
had be
Glucocorticoids
1985b) and immune complexes ( V i r g i n et a l . ,
no effect
blocked (Warren
by and
1985) were also e f f e c t i v e
i n h i b i t o r s of class II a n t i g e n e x p r e s s i o n by gamma i n t e r f e r o n , the l a t t e r only if the Fc p o r t i o n of the a n t i b o d y molecule was i n t a c t . Complexes composed of IgG1,
IgG2a,
IgG2b and
IgM o r IgA were not. 1982a),
dibutryl
interferon.
Endotoxin
macrophages prostaglandin
to
but
those c o n s i s t i n g of e i t h e r
P r o s t a g l a n d i n E 2 (Gershon et a l . ,
cAMP
1982a) also i n h i b i t e d
IgE were e f f e c t i v e , (Steeg
,~.t a l . ,
the i n d u c t i o n of class undoubtedly
secrete
synsthesis,
PGE 2,
the
(Steeg et a l . ,
II a n t i g e n e x p r e s s i o n by gamma
mediated
because
reversed
1985; Steeg et a l . ,
1982a) and e n d o t o x i n its
effects
indomethacin, inhibitory
by an
effect
in
stimulating inhibitor
of
experiments
p e r f o r m e d by Steeg and h e r colleagues (1982a). The
interferons
were also able to
class I MHC a n t i g e n s (Kelley et a l . , 1983, 1984; Yoshie et a l . ,
1982).
up-regulate
the e x p r e s s i o n of
1984; K i n g and Jones, 1983; Wong et a l . ,
In c o n t r a s t to class II MHC a n t i g e n s , those
of class I were induced on a v a r i e t y of cell t y p e s by a n y of the t h r e e classes of i n t e r f e r o n
(Kelley et a l . ,
1984).
Expression was e n g e n d e r e d on cells
in
143
vivo,
as
well
as
Rhodes et a l . , antigen
of
regulated antigens
vitro
on
different
these
two
et a l . ,
independently
cell
classes (Wong
Nakamura et a l . ,
1984;
1985). Dissociation of class I and II
types of
et
1986;
suggested
major
al.,
that
interferon
histocompatibility
1984).
The
finding
driven
antigen that
was
class
II
were induced by gamma i n t e r f e r o n p r i m a r i l y on cells of the immune
system ( K i n g and Jones, this
(Momburg
1983; Skoskiewicz et a l . ,
induction
expression
in
1983; Wong et a l . ,
1983,
1984) was c o n s i s t e n t w i t h
l y m p h o k i n e ' s known c a p a c i t y to enhance immunologic responses ( B e c k e r ,
1985; Nakamura et a l . , 4.3
1984; Sztein et a l . , 198q).
Maintenance and
Enhancement of
Interleukin
1 (IL-1)
Secretion by
Interferons Another through study
their
way
effect
(Boraschi
et
that
on al.,
interferons
IL-1
can
secretion
1984),
affect
the
immune response is
by mononuclear p h a g o c y t e s .
gamma
but
not
alpha
interferon
In one directly
stimulated the p r o d u c t i o n o f IL-1 by mouse r e s i d e n t p e r i t o n e a l macrophages. In a n o t h e r instance ( A r e n z a n a - S e i s d e d o s and V i r e l i z i e r , alone
were
interferons
not
able
to
stimulate
secretion;
had an e n h a n c i n g e f f e c t .
Again
most efficacious of the t h r e e t y p e s .
1983), the i n t e r f e r o n s
however,
here,
The a b i l i t y
any
one
of
the
gamma i n t e r f e r o n was the to secrete
IL-1
is lost by
mononuclear phagocytes when t h e y are maintained in c u l t u r e . The i n t e r f e r o n s , particularly
gamma,
have
the
capacity
to
maintain
such s e c r e t o r y c a p a c i t y
( A r e n z a n a - S e i s d e d o s et a l . , 1985; Haq et a l . ; 1985). 4,4
Arachidonate
Metabolism,
Includin~l
Prostaglandin
and
Leukotriene
Synthesis and Secretion The p r o d u c t s of a r a c h i d o n i c acid metabolism are i m p o r t a n t both as immunoregulatory
and
inflammatory
mediators.
Thus,
by
influencing
the
secretion of these metabolites, the i n t e r f e r o n s influence both the immune and i n f l a m m a t o r y responses. As w i t h I L - 1 , mononuclear
phagocytes
to
none of the i n t e r f e r o n s alone induced
secrete
either
cyclooxygenase/lipoxygenase metabolites. significantly
enhance
secretion
d i e s t e r s (Boraschi et a l . ,
induced
arachidonic
However, by
some
1985; Hamilton et a l . ,
acid
gamma stimuli,
or
its
interferon
did
notably
phorbol
1985). Whether secretion that
is caused b y o t h e r s t i m u l i , such as zyrnosan, insoluble immune complexes o r the calcium ionophore, A23187, due to c o n f l i c t i n g and
his
results
colleagues
is a l t e r e d b y the i n t e r f e r o n s is still u n c l e a r ,
reported
(1985)
in the l i t e r a t u r e .
reported
that
secretion
For example, Hamilton of
arachidonic
acid
metabolites from e l i c i t e d mouse p e r i t o n e a l macrophages p r e t r e a t e d w i t h gamma interferon
and
then
stimulated
with
the
calcium
ionophore,
A23187,
was
144
unaltered.
In
pretreatment
apparent of
direct
resident,
contrast,
i.e.,
Boraschi
unstimulated,
et
al.
(1985)
found
that
mouse peritoneal macrophages
w i t h gamma i n t e r f e r o n i n h i b i t e d a r a c h i d o n i c acid and l e u k o t r i e n e C 4 release by A23187,
but
greatly
increased the release of the c y c l o o x y g e n a s e p r o d u c t s ,
PGE 2 and 6 - k e t o PGF 1 a l p h a . The two g r o u p s d i f f e r e d s i m i l a r l y w i t h r e g a r d to release
stimulated
pretreated
with
decrease,
while
evaluation
of
macrophages
gamma
interferon:
Hamilton
the
metabolism by
from
and
effects
his
of
by
zymosan
Boraschi
and
associates
alpha/beta
after her
found
had
colleagues no
interferons
they effect.
on
been
noted
a
The
only
arachidonic
acid
macrophages has been made by Boraschi et al.
(1984,
1985).
P r e t r e a t m e n t of the cells w i t h alpha o r beta i n t e r f e r o n s d r a m a t i c a l l y decreased arachidonic
acid
liberation
from
membrane
phospholipids,
as
well
as
the
formation of c y c l o o x y g e n a s e and l i p o x y g e n a s e p r o d u c t s , a f t e r s t i m u l a t i o n . 5.0
INFLUENCE
OF
INTERFERONS
ON
MONONUCLEAR
PHAGOCYTE
EFFECTOR FUNCTIONS 5.1
Chemotaxis, Fc and C3 Receptor E x p r e s s i o n , and Phacjocytosis Macrophages
differentiate
in
inflammatory
reactions
predominantly
from monocytes t h a t are mobilized from the blood. Once monocytes leave the v a s c u l a r system, they c r a w l along stromal elements, such as collagen f i b e r s , following
a
gradient
of
chemotactic
stimuli
that
diffuse
out
from
the
inflammatory s i t e . Alpha i n t e r f e r o n has been shown to decrease both random (chemokinetic) and d i r e c t e d (chemotactic) m i g r a t i o n of monocytes (Ohmann and Babiuk,
1984). Whether o r not this has a n y t h i n g to do w i t h i n t e r f e r o n acting
as m i g r a t i o n i n h i b i t o r y
factor
both alpha ( T h u r m a n et a l . , et a l . ,
1984) i n t e r f e r o n s ,
(MIF),
an a c t i v i t y
t h a t has been a s c r i b e d to
1985) and gamma ( T h u r m a n et a l . ,
1985, Varesio
is a question t h a t needs f u r t h e r e x p l o r a t i o n . In its
M I F - l i k e role; gamma was more p o t e n t than alpha i n t e r f e r o n ( T h u r m a n et a l . , 1985). Beta i n t e r f e r o n increased s p r e a d i n g p r o p e r t i e s of macrophages (Rollag and Degre, 1982). Once
at
p h a g o c y t i c cells
the
site of
inflammation,
one of
is e n g u l f m e n t of p a r t i c u l a t e m a t e r i a l .
removal of d e b r i s and f o r e i t h e r be opsonized o r not.
the
main
k i l l i n g of ingested m i c r o o r g a n i s m s . Degre and
Rollag (1982)
functions
of
The need is both f o r Particles can
have shown t h a t beta
i n t e r f e r o n will stimulate the u p t a k e of unopsonized Escherichia coil b a c t e r i a by mouse
peritoneal
Staphylococcus bovine
monocytes
B a b i u k , 1984).
macrophages.
aureus and
bacteria
Phagocytosis was similarly
macrophages
with
of
opsonized
stimulated by
alpha
interferon
E.
coli
and
p r e t r e a t m e n t of (Ohmann
and
145
The opsonins t h a t p r i n c i p a l l y mediate u p t a k e of p a r t i c u l a t e material by
mononuclear phagocytes are a n t i b o d y and cleavage p r o d u c t s of the t h i r d
component of complement. Two complement r e c e p t o r s have been examined w i t h r e g a r d to the effects t h a t i n t e r f e r o n s have on them: CR I (C3b r e c e p t o r ) and CR III
(C3bi r e c e p t o r ) .
mononuclear
phagocytes
phagocytes
to
(Becket
al.,
et
The Mac-1 epitope is on the C3bi r e c e p t o r of mouse (Belier
interferon 1983
et
al.,
either
[alpha
[ g a m m a ] ; Wright et a l . , [beta];
has
or
1982).
caused
Exposure
reduced
gamma i n t e r f e r o n s ] ;
1985a [ a l p h a / b e t a ] ;
mononuclear of
CR
Esparza et a l . ,
1986 [ g a m m a ] ) and CR I l l / M a c - 1
Warren and V o g e l ,
of
expression
(Vogel et a l . ,
Wright et a l . ,
I
1986 1983a
1986 [gamma])
o r has had no d e t e c t a b l e e f f e c t on the e x p r e s s i o n of these r e c e p t o r s ( B e c k e t et a l . , al.,
1983 [ b e t a
interferon];
1986 [ g a m m a ] ) .
Esparza et a l . ,
1986 [ g a m m a ] ;
P a p i e r n i k et
The s u g g e s t i o n has been made that reduced b i n d i n g to
CR I is not due to i n t e r n a l i z a t i o n of the r e c e p t o r (Esparza et a l . ,
1986). The
a u t h o r s based this conclusion on t h e i r f i n d i n g that both plasma membrane and i n t r a c e l l u l a r pools of r e c e p t o r decreased a f t e r t r e a t m e n t w i t h i n t e r f e r o n . This interpretation
should
be
revisited,
however,
because c o n s i d e r a t i o n
was not
g i v e n to the p o s s i b i l i t y t h a t r e c e p t o r could have been d e g r a d e d a f t e r it was i n t e r n a l i z e d . Whatever the cause of the reduced b i n d i n g , within
it can be r e v e r s e d
45 minutes by a l l o w i n g macrophages to spread on a surface coated w i t h
f i b r o n e c t i n ( W r i g h t et a l . , 1986). In c o n t r a s t to the s u p p r e s s i v e effect t h a t i n t e r f e r o n s g e n e r a l l y have on the b i n d i n g of complement components, the general f i n d i n g has been that i n t e r f e r o n t r e a t m e n t increases Fc-mediated b i n d i n g of a n t i b o d y to mononuclear phagocytes ( B e c k e t et a l . , Perussia et a l . , 1983b;
Wang
complete
1983; Esparza et a l . ,
1983b; Ralph et al,
et
al.,
concurrence,
1984; the
1986; C u y r e et a l . ,
1983; Rhodes et a l . ,
Yoshie
et
al.,
phenomenon
1982).
appears
increased e x p r e s s i o n of the r e c e p t o r s ( G u y r e et a l . , 1983b; Vogel et a l . , RNA
and
protein
disagreement with
1983b; Yoshie et a l . , synthesis
(Yoshie
this conclusion
et
1983; Vogel et a l . ,
Although
most
1983 ;
likely
there to
is
not
be due
to
1983 ; Perussia et a l . ,
1982), which depends on c o n t i n u e d al.,
1982).
(Wang et a l . ,
The
one
report
in
1984) d e s c r i b e d no increase
when FcR II r e c e p t o r e x p r e s s i o n was q u a n t i f i e d using the Fab f r a g m e n t of an a n t i - r e c e p t o r monoclonal a n t i b o d y .
When it has been measured, no change in
Fc
been found
receptor
binding
( G u y r e et a l . ,
affinity
has
1983 ; Perussia et a l . ,
following
interferon
treatment
1983b). U p - r e g u l a t i o n of Fc r e c e p t o r s
by the i n t e r f e r o n s seems to be b r o a d l y applicable to myeloid cells, e . g . , mature n e u t r o p h i l s can be a f f e c t e d p o s i t i v e l y (Perussia et a l . , same s t u d y ,
even
1983b). In the
t h e r e was no d e t e c t a b l e effect on the e x p r e s s i o n of Fc r e c e p t o r s
by neoplastic cells of l y m p h o i d lineage.
146
As one m i g h t e x p e c t , changes in the e x p r e s s i o n of r e c e p t o r s on the surfaces of mononuclear phagocytes a l t e r the p h a g o c y t i c c a p a b i l i t i e s of these cells.
Uptake
1984a,b;
of
zymosan
Becker
et a l . ,
is
decreased
1983).
Whether
by
interferon
this
phenomenon is a t t r i b u t a b l e to
treatment
reduced e x p r e s s i o n / f u n c t i o n of the complement r e c e p t o r s ,
(Becker,
to a r e d u c t i o n in
e x p r e s s i o n of the mannosyl, fucosyl r e c e p t o r (Mokoena and G o r d o n , both,
is not k n o w n .
r e c e p t o r s on i n t e r f e r o n - t r e a t e d
macrophages,
ingestion d i d not ensue unless
t h e r e was f u r t h e r stimulation of the cells, e . g . , (Wright
et
al.,
greatly
enhanced
endogenously
1985), or
Even when b i n d i n g c a p a b i l i t y is r e s t o r e d to complement
1986). by
Fc-mediated interferon
produced
by one of the phobol d i e s t e r s
phagocytosis,
treatment.
alpha/beta
As
on
the
other
mentioned
interferons
may
in
be
hand,
section
critical
is 3.3,
to
the
development of Fc r e c e p t o r - m e d i a t e d p h a g o c y t i c c a p a b i l i t i e s b y d i f f e r e n t i a t i n g mononuclear phagocytes (Moore et a l . ,
1985; Vogel and F e r t s c h ,
1984). Once
macrophages have developed such a c a p a b i l i t y , the role of the i n t e r f e r o n s may be
to
enhance
this
important
inflammatory r e a c t i o n .
host
defense
In one s t u d y ,
both
mechanism at
the
site
the rate of p h a g o c y t o s i s and the
total u p t a k e of p a r t i c l e s by macrophages were increased (Wang et a l . , All
three
interferon
types
have
been
of an
effective,
although
1984).
gamma i n t e r f e r o n
again seems to be the most e f f e c t i v e . Both the FcR I and FcR II r e c e p t o r s f o r mouse
IgG
were
affected
(Vogel
et
al.,
1983b).
The
enhancement of
Fc
r e c e p t o r - m e d i a t e d phagocytosis by gamma i n t e r f e r o n was increased even more by
the a d d i t i o n of c o r t i c o s t e r o i d s (Warren and V o g e l ,
1985b). The effect on
Fc r e c e p t o r - m e d i a t e d p h a g o c y t o s i s seemed to be r e g u l a t e d s e p a r a t e l y from t h a t of
the
antiviral,
interferons
antiproliferative
( F e r t s c h and Vogel,
m i c r o t u b u l e s and
and
these
findings,
activating
1984; Vogel et a l . ,
activities
of
the
1986). U l t r a s t r u c t u r a l l y ,
10 nm filaments a g g r e g a t e d in the p e r i n u c l e a r cytoplasm of
macrophges t r e a t e d w i t h beta i n t e r f e r o n , of
NK
elements
beneath
the
in association w i t h r e l a t i v e c l e a r i n g
plasmalemma
together with other indicators,
(Wang
et
al.,
1984).
These
led Wang and colleagues to conclude
t h a t enhancement of Fc r e c e p t o r - m e d i a t e d p h a g o c y t o s i s was due to accelerated association of actin filaments w i t h the plasma membrane d u r i n g the e n g u l f m e n t of p a r t i c l e s . 5.2
Activation for killing 5.2. I
Macrophage a c t i v a t i n g f a c t o r ( s ) and i n t e r f e r o n s The
morphologically macrophages
by
from
activated
state
in
macrophages
was
George Mackaness while he was w o r k i n g mice
infected
with
Listeria
first
recognized
with
monocytogenes
peritoneal
(Mackaness,
147
1962).
He
noted
subsequently
immunologically
specific
caused
rapid
a more
that
induction
of
the
activated
state
is
(second e x p o s u r e of a mouse to the same organism onset
of
activation,
and
t h i s c h a r a c t e r i s t i c could be
t r a n s f e r r e d a d o p t i v e l y to a naive mouse w i t h immune l y m p h o c y t e s ) ; that once macrophages were a c t i v a t e d they c o n f e r r e d p r o t e c t i o n n o n s p e c i f i c a l l y against a range of a n t i g e n i c a l l y u n r e l a t e d p a t h o g e n s ; and he speculated t h a t a c t i v a t i o n was
induced
1969;
Miki
by
a secretory
and
Mackaness,
product(s) 1964).
of
As
lymphocytes
will
be
seen
(Mackaness,
in
the
1964,
following
two
sections, Mackaness ~ f i n d i n g s have been e x t e n d e d and r e f i n e d d u r i n g the past twenty years.
However,
his
initial c o n t r i b u t i o n s are remembered as some of
the most i m p o r t a n t and seminal in the f i e l d . The soluble p r o d u c t of l y m p h o c y t e s a b o u t which Mackaness speculated factor,
was
later
identified
and
o r MAF (Piessens et a l . ,
given working
MAF would not a c t i v a t e macrophages f o r signal
(Weinberg
et
Weinberg
(endotoxin,
al.,
et al.
1978).
name macrophage a c t i v a t i n g
1975). A few y e a r s l a t e r ,
Brice Weinberq and his colleagues, triggering
the
in
their
However,
it
it was shown by
in John Hibbs ~ l a b o r a t o r y , t h a t
t u m o r cell k i l l i n g unless a second, case)
was
is now
present
known
that
in
the
the
medium
f i n d i n g s of
do not a p p l y e q u a l l y to all k i n d s of m a c r o p h a g e - m e d i a t e d ,
nonspecific k i l l i n g because t a r g e t s and the levels of a c t i v a t i o n needed to deal with
them a p p a r e n t l y d i f f e r .
One must s p e c i f y ,
therefore,
the p u r p o s e for
which a macrophage is a c t i v a t e d when the term is used, e . g . ,
activation for
t u m o r cell k i l l i n g o r f o r l i s t e r i a c i d a l a c t i v i t y . A
major advance
in
the
field
was the
d e m o n s t r a t i o n in a
l a r g e n u m b e r of l a b o r a t o r i e s d u r i n g 1982-83 that one, i f not the main, form o f MAF is gamma i n t e r f e r o n M u r r a y et a l . , 1983a,b; 1983;
( K l e i n s c h m i d t and S c h u l t z ,
1983; Nathan et a l . ,
Roberts and V a s i l ,
Schultz
and
1982;
1983; O r t a l d o et a l . ,
1982; Rothermel et a l . ,
Kleinschmidt,
Le et a l . ,
1983;
1983; Pace et a l . ,
1983; S c h r e i b e r et a l . ,
1983; Wisseman and Waddell,
1983).
These
i n i t i a l r e p o r t s have since been c o n f i r m e d and e x t e n d e d b y a d d i t i o n a l in v i t r o (Le and V i l c e k , et a l . ,
1984; Ockenhouse et a l . ,
1985; S p i t a l n y and Havell,
Winkler,
1984; U t s u g i and Sone,
(Buchmeier and S c h r e i b e r , studies.
In r e t r o s p e c t ,
1984; Passwell et a l . ,
1984; S v e d e r s k y et a l . ,
1986; and Varesio et a l . ,
1985; K i d e r l e n et a l . ,
1986; Sadlik
1984; T u r c o and 1984a) and in v i v o
1984; M u r r a y et a l . ,
1985)
it should not have been s u r p r i s i n g to d i s c o v e r in the
1980s t h a t at least one k i n d of MAF and i n t e r f e r o n
are the same: Richard
Schultz,
had
working
in
Michael
Chirigos ~ laboratory,
already
published
several p a p e r s in the late 1970s t h a t showed s i m i l a r i t i e s between macrophage activating Schultz
f a c t o r and c r u d e p r e p a r a t i o n s of i n t e r f e r o n and
Chirigos,
1978,
1979).
Before
this,
(Schultz et a l . ,
Samuel
Salvin
and
1977; his
148
colleagues had shown t h a t mice w i t h d e l a y e d - t y p e h y p e r s e n s i t i v i t y reactions had both
interferon
and m i g r a t i o n i n h i b i t o r y
sera (Salvin et a l . ,
f a c t o r (MIF) a c t i v i t i e s in t h e i r
1973). As has a l r e a d y been mentioned, alpha and gamma
i n t e r f e r o n s can mediate MIF a c t i v i t y
( T h u r m a n et a l . ,
1985; Varesio et a l . ,
1984a). Alpha and beta i n t e r f e r o n s , had
activating
capabilities
(Dean
1982). They were less e f f i c i e n t ,
and
in a d d i t i o n to gamma, have also
Virelizier,
1983;
Herberman
et
al.,
h o w e v e r , when compared w i t h gamma on the
Sone, 1986). Cytokines i.e.,
have
the
infectious
capacity
agents
conditioned
and
medium
(Hoover et a l . ,
other
than
tumor
(Wing
cells.
et
1983)
and
1982),
1984; Lee et a l . ,
supernates
of
T
have
may also be MAFs, the k i l l i n g of v a r i o u s
been
lymphocyte
found culture
in
L
cell
supernates
1985), s u p e r n a t e s of l y m p h o c y t e cell lines 1986; and Meltzer et a l . ,
cloned T l y m p h o c y t e s ( A n d r e w et a l . , al.,
interferons
These
al.,
1986; Nacy et a l . ,
(Kleinerman et a l . ,
the
to a c t i v a t e macrophages f o r
1984; Gemsa et a l . ,
lymphocyte
1982), those of
1983; Krammer et
hybridomas
( K r a m m e r et
al.,
1983). Some of these r e p o r t s a r e h i g h l y c o n v i n c i n g ; h o w e v e r , o t h e r s must be viewed w i t h
reservations,
concentrations
below
for the f o l l o w i n g reasons. F i r s t ,
one
unit
can
have
marked
gamma i n t e r f e r o n
activating
effects
on
macrophages u n d e r a p p r o p r i a t e c o n d i t i o n s . Given t h a t the a n t i v i r a l assay f o r i n t e r f e r o n is not p a r t i c u l a r l y s e n s i t i v e , i n a b i l i t y to d e t e c t a n t i v i r a l a c t i v i t y in a p r e p a r a t i o n t h a t has macrophage a c t i v a t i n g a c t i v i t y that
interferon
is
not
present.
Second,
a c t i v a t i n g agents from i n t e r f e r o n activators
could
claims
of
is not clear evidence physical
separation
of
can be questioned on the basis t h a t small
be cleavage f r a g m e n t s
of
interferon.
To date,
we do not
know w h e t h e r o r not i n t e r f e r o n molecules contain separate f u n c t i o n a l domains. If they do, it is conceivable t h a t a f r a g m e n t could have a c t i v a t i n g c a p a b i l i t i e s without
antiviral
antibody
to
interferon.
bind
activity.
Third,
an a c t i v a t o r
failure
of
a
is not p r o o f that
monoclonal
anti-interferon
the a c t i v a t o r d i f f e r s
S u f f i c i e n t a n t i g e n i c d i f f e r e n c e s e x i s t between d i f f e r e n t
from
regions of
the i n t e r f e r o n molecule t h a t a monoclonal a n t i b o d y could b i n d one f r a g m e n t of i n t e r f e r o n b u t not a n o t h e r (Russell, J . , et a l . ,
1986). F o u r t h , the f i n d i n g of
d i f f e r e n c e s in the s p e c t r u m of functional a c t i v i t i e s induced by M A F - c o n t a i n i n g supernates from d i f f e r e n t
T cell clones is not s u f f i c i e n t
to conclude t h a t a
d i f f e r e n c e e x i s t s between two p u t a t i v e a c t i v a t o r s . The a c t i v i t y of each such supernate
is
the
net
of all
of
the
i n d i v i d u a l T cell clone, not just MAF.
lymphokines
that
are
p r o d u c e d by an
O t h e r c y t o k i n e s could be p r e s e n t t h a t
modify the effect of MAF in biological assays, such as t u m o r cell k i l l i n g . While
149
t h e s e c a v e a t s must MAFs
other
issue.
than
be c o n s i d e r e d interferon,
one c l e a r l y
must
whether or not there are
keep
an
open
mind on t h e
No one has y e t p r o d u c e d a c o m p e l l i n g a r g u m e n t as to w h y t h e r e should
be o n l y one M A F . cloned,
However,
L l o y d OId's p a r a p h r a s e o f D e s c a r t e s ,
therefore
it e x i s t s '~ ( O l d ,
reminder
that
technology
activators
are
the the
thereof).
Those
interferon
will
to
rigorous
have
purification
existence
of
extant
to
different
who
to
their
have
than
unequivocally
an
investigations
and c h a r a c t e r i z a t i o n MAF
prove
t h a n one o f t h e
claim
extend
another
"It's
been
1985), s h o u l d be r e g a r d e d as a h u m o r o u s
is
same as o r
derivative
the
w h e n assessing
activator to
the
or cloning and
one
of
the
whether
interferons
(or a
other
level
than
of
either
sequencing
before
interferons
can
be
fully
accepted. 5.2.2
Macrophacje-mediated microbicidal activity O x y g e n d e p e n d e n t and i n d e p e n d e n t m i c r o b i c i d a l p r o d u c t s a r e
produced
by
macrophages
(Ockenhouse
et
identified
phagocytic
1980).
in
al.,
in
response
1984). cells
The
to
most
is t h e
stimulation important
so-called
by
gamma
killing
K l e b a n o f f system
It is d e p e n d e n t on t h e i n t e r a c t i o n o f h y d r o g e n
interferon
mechanism
yet
(Klebanoff,
peroxide (H202)
with
one o f the h a l i d e ions and p e r o x i d a s e . Gamma i n t e r f e r o n e n h a n c e d the a b i l i t y t h a t m a c r o p h a g e s had to p r o d u c e H20 2 ( M u r r a y
et a l . ,
1983; N a t h a n et a l . ,
1983). With t h e e x c e p t i o n o f MIF, w h i c h may e i t h e r be t h e same as o r r e l a t e d to gamma i n t e r f e r o n
( T h u r m a n et a l . ,
of other cytokines,
including
e i t h e r to s t i m u l a t e H20 2 p r o d u c t i o n T o x o p l a s m a ( N a t h a n et a l . ,
or
were
et a l . ,
required;
1984), a v a r i e t y lacked the ability
to increase t h e i n t r a c e l l u l a r k i l l i n g o f
to i n d u c e e i t h e r a maximal m i c r o b i s t a t i c h o u r s to d a y s o f s t i m u l a t i o n
no e f f e c t was seen i f m a c r o p h a g e s w e r e i n f e c t e d b e f o r e t h e y
R o t h e r m e l et a l . ,
( M u r r a y et a l . ,
1983; N a t h a n et a l . ,
1983;
1983). Although
provide
interferons,
1983) o r m i c r o b i c i d a l e f f e c t ,
w e r e e x p o s e d to gamma i n t e r f e r o n
often
beta
1984).
F o r gamma i n t e r f e r o n (Rothermel
1985; V a r e s i o et a l . ,
alpha and
either
macrophages with
gamma
interferon
or
l y m p h o k i n e alone can
an e f f e c t i v e a n t i m i c r o b i a l s t i m u l u s ,
in o t h e r
i n s t a n c e s t h e r e is t h e r e q u i r e m e n t f o r a second signal ( B u c h m u l l e r and Mauel, 1979;
K r a m m e r et a l . ,
vitro
by
activating
mediate c y t o t o x i c i t y is
an
important
1985). When m a c r o p h a g e s a r e no l o n g e r s t i m u l a t e d in
factors,
at
least
in
some instances
their
capacity
is lost o v e r a p e r i o d o f d a y s ( N a t h a n et a l . ,
consideration,
because
loss
of
the activated
to
1983). T h i s
state
in
vivo
w o u l d mean t h a t m a c r o p h a g e s w o u l d h a v e d i m i n i s h e d h o s t d e f e n s e c a p a b i l i t i e s . One
mechanism b y
which
macrophages could
be d e p r i v e d
in v i v o o f gamma
150
interferon
in t h e i r
e n v i r o n m e n t is t h r o u g h
t h e n e g a t i v e r e g u l a t o r y e f f e c t of
PGE 2 on l y m p h o k i n e p r o d u c t i o n b y T l y m p h o c y t e s ( E d w a r d s et a l . , 5.2.3
1986).
N o n s p e c i f i c k i l l i n 9 of t u m o r cells Many of the f e a t u r e s of macrophages a c t i v a t e d f o r t h e k i l l i n g
of m i c r o o r g a n i s m s a r e s h a r e d b y m a c r o p h a g e s a c t i v a t e d to k i l l t u m o r c e l l s . fact,
most of
macrophages
the c h a r a c t e r i s t i c s (see
section
h a v e been a c t i v a t e d The
for
first
5.2.1, the
described
above)
killing
apply
equally
to m a c r o p h a g e s t h a t
of e i t h e r m i c r o o r g a n i s m s o r t u m o r c e l l s .
r e m a i n d e r of t h i s r e v i e w summarizes f i n d i n g s
t u m o r cells as the t a r g e t f o r k i l l i n g . findings
In
b y Mackaness f o r a c t i v a t e d
t h a t h a v e been made w i t h
It is l i k e l y ,
however,
a r e g e n e r a l l y a p p l i c a b l e to t h e a c t i v a t e d s t a t e ,
t h a t many of t h e
g i v e n the s i m i l a r i t i e s
t h a t e x i s t b e t w e e n a c t i v a t i o n f o r k i l l i n g m i c r o o r g a n i s m s and t u m o r c e l l s . Mixtures interferon
can
interferon
of
gamma
be more e f f i c i e n t
used
alone
(Pace
in
et
interferon inducing
al.,
and
either
alpha
tumoricidal activity
1985;
Schultz,
or
beta
than either
1982).
Quantitative
c o m p a r i s o n s of the a c t i v a t i n g effects o f i n t e r f e r o n s and m i x t u r e s o f them h a v e revealed
that
interferon were
priming
can
the
yield
response
activating
effects
in
results
between such
used
in
the
vitro
condition
mixtures
strictly
by
the
of
of
(Pace
interferons
and
laboratories
are
investigations.
likely
alpha
et
al.,
1985).
or
cell
beta
killing,
Potentiation
of
has not a l w a y s been d e t e c t e d , due
1981). Such d i f f e r e n c e s
to
differing
experimental
m a t u r a t i o n a l state of the macrophages
Whether o r
r e l e v a n c e to h o s t
either
a m o u n t of t u m o r
1984; Boraschi and T a g l i a b u e ,
as t h e source a n d / o r has
gamma
predicted
additive
mixtures
h o w e v e r (Blasi et a l . , conditions,
by
more t h a n
not p o t e n t i a t i o n o b s e r v e d
under
in
defense in v i v o is n o t y e t k n o w n and
must be d e t e r m i n e d if we a r e to u n d e r s t a n d f u l l y the r e g u l a t i o n of a c t i v a t i o n in t h e l i v i n g a n i m a l . Interferon-induced killing
results
current
time,
rather
activation of macrophages for
in a c o n s t e l l a t i o n o f s u b c e l l u l a r these must
be r e g a r d e d as c h a n g e s
t h a n c a u s a l l y r e l a t e d to,
t u m o r cell
biochemical c h a n g e s .
t h e process o f a c t i v a t i o n .
The f i r s t
of an associated biochemical c h a n g e is one o b s e r v e d b y B o n v i n i et a l . In
this
interferon
study,
treatment
of
murine
macrophages
At
the
t h a t a r e associated w i t h ,
with
recombinant
example (1986). gamma
caused an increase in i n t r a c e l l u l a r levels of S - a d e n o s y l m e t h i o n i n e ,
w i t h no a p p a r e n t i n h i b i t i o n of p h o s p h o l i p i d m e t h y l a t i o n , c o n c o m i t a n t w i t h t h e acquisition of tumoricidal activity. macrophages refractory
T h e d e p l e t i o n o f S - a d e n o s y l m e t h i o n i n e made
to a c t i v a t i o n b y gamma i n t e r f e r o n .
These f i n d i n g s a r e
in c o n t r a s t to o b s e r v a t i o n s made o f human p e r i p h e r a l blood m o n o n u c l e a r cells t r e a t e d w i t h e i t h e r a l p h a o r beta i n t e r f e r o n ( B o u g n o u x et a l . ,
1982). In these
151
earlier
studies,
i n t r a c e l l u l a r pools of S - a d e n o s y l m e t h i o n i n e were u n a f f e c t e d ,
while the m e t h y l a t i o n o f p h o s p h a t i d y l e t h a n o l a m i n e was i n h i b i t e d . The d i f f e r i n g results
could
be e x p l i c a b l e on
several
bases,
including
differences
in the
species from which the cells came, d i f f e r e n t p o p u l a t i o n s of cells and times of treatment, critical
as well as d i f f e r e n t
one.
For instance,
interferons.
The l a t t e r d i f f e r e n c e can be a
Blasi and h e r colleagues (1984) found that mouse
peritoneal
macrophages
treated
synthesis,
developed c y t o l y t i c
with
cycloheximide,
to
prevent
protein
a c t i v i t y in response to gamma i n t e r f e r o n ,
but
d i d not i f the a c t i v a t i n g a g e n t was e i t h e r alpha or beta i n t e r f e r o n . Changes receiving
close
because
of
in c e l l u l a r p r o t e i n s induced by the i n t e r f e r o n s are
scrutiny.
the
Protein
general
phosphorylation
importance
this
is of
biochemical
r e g u l a t i o n of many i n t r a c e l l u l a r processes. Weiel et al. four
proteins
masses
that
in macrophages of are
28,
phosphorylated
33,
particular
reaction
interest
has
in
the
(1986) have i d e n t i f i e d
37 and 67 kDa a p p a r e n t molecular
after
mouse
peritoneal
macrophages
are
t r e a t e d with e i t h e r b a c t e r i a l l i p o p o l y s a c c h a r i d e (LPS), p h o r b o l e s t e r o r gamma i n t e r f e r o n and LPS. A l t h o u g h they d i d not measure t u m o r i c i d a l a c t i v i t y in this study, were
the amounts o f LPS a n d , e s p e c i a l l y , gamma i n t e r f e r o n plus LPS that used
killing. that were
should
Work
protein
have been s u f f i c i e n t
from this
to induce a c t i v a t i o n and
same l a b o r a t o r y
(Hamilton et a l . ,
tumor cell
1985a) suggested
kinase C may be a c t i v a t e d in mouse peritoneal cells when they
treated
with
gamma
interferon,
a c t i v a t o r s of p r o t e i n kinase C ) , peritoneal
macrophages
relevance
of
observations
these by
for
Johnson
and
that
phorbol
esters
(known
t o g e t h e r w i t h calcium ionophore, could prime
tumor
findings
and
cell
remains Tortes
killing
(Somers
to
determined
be
et
(1985) and Wright
al., in
1986). light
et al.
The
of
(1985)
the that
calcium i o n o p h o r e alone could s u b s t i t u t e in t h e i r studies f o r gamma i n t e r f e r o n in the a c t i v a t i o n p r o c e s s . Quantitative
and
qualitative
changes
in
the
expression
of
p r o t e i n s in macrophages t r e a t e d w i t h a c t i v a t i n g agents have also been sought (Mackay
and
Russell,
separation
of
three
could
that
1986).
35S-methionine be used
By
means of
two dimensional e l e c t r o p h o r e t i c
labeled p r o t e i n s ,
to c o n s t r u c t
these i n v e s t i g a t o r s
phenotypes
that
mark
the
identified various
stages of macrophage a c t i v a t i o n . The p r o t e i n p47b (47 kDa a p p a r e n t molecular mass)
was
exposing
expressed
them
by
mouse
macrophages
to one of the i n t e r f e r o n s .
when cells were t r e a t e d w i t h
LPS,
that
This
Cellular
been
"primed"
by
was also e x p r e s s e d
b u t o n l y because such t r e a t m e n t caused
the macrophages to secrete a l p h a / b e t a i n t e r f e r o n s , p r i m e d the cells;
had
protein
which then stimulated and
p r o t e i n s t h a t were a l t e r e d in t h e i r e x p r e s s i o n by
e x p o s u r e o f macrophages to a second, t r i g g e r i n g a g e n t ,
such as e i t h e r heat
152
killed
Listeria
associated
with
monocytocjenes
or
activation,
and p73 (71 and
p71
LPS,
included
two
that
73 kDa,
were
closely
respectively).
It
remains to be shown w h e t h e r o r not t r i g g e r i n g t h a t is associated w i t h o t h e r compounds (Hamann
and and
phenotypes, pq7b
mediators, ~ i n c l u d i n g
but
Krammer,
not
contained
1985),
Mackay and
all
p71/73, three
Russell while
proteins.
lymphokines
induce
other
expression
than
of
interferon
p71/73.
As
to
showed that primed macrophages e x p r e s s e d
mouse macrophages that Expression
of
these
were
proteins
fully
activated
waned
in v i t r o
concomitant w i t h loss of c y t o l y t i c a c t i v i t y a f t e r a c t i v a t o r s had been removed. The a b i l i t y to q u a n t i f y a c t i v a t i o n stages in v i v o , i . e . ,
in lesions, could o f f e r
a new approach to e v a l u a t i n g the efficacy of immunomodulators. A biochemical change t h a t is associated w i t h and q u i t e l i k e l y involved
in
calcium.
activation
is an
increase
in
the
concentration
of
One piece of evidence Elready mentioned is t h a t calcium ionophore
can s u p p l y one o r more a c t i v a t i o n signals (Johnson and T o r r e s , et
al.,
intracellular
1985;
Wright
et a l . ,
1985).
Whether
this
is
due
1985; Somers
to an
influx
of
e x t r a c e l l u l a r calcium o r to the r e d i s t r i b u t i o n of i n t r a c e l l u l a r stores is not y e t c l e a r . Wright et al. (1985) have shown t h a t i n t e r f e r o n / L P S - m e d i a t e d a c t i v a t i o n of
mouse
peritoneal
dose-dependent extracellular McCulloch
calcium
(1986),
macrophage 45calcium
cell
during
macrophages
fashion
by
is
for
calcium
important.
studying line,
tumor
cell
channel
killing
is
blockers,
On the o t h e r h a n d ,
inhibited
in
suggesting
that
G o r e c k a - T i s e r a and
the l y m p h o k i n e - m e d i a t e d a c t i v a t i o n of the mouse
RAW
264,
could
detect
activation,
and
three
different
no
increase
channel
in
uptake
blockers
had
of no
effect on the a b i l i t y of l y m p h o k i n e / L P S to induce the e x p r e s s i o n of t u m o r i c i d a l activity.
Furthermore,
G o r e c k a - T i s e r a and her colleagues have demonstrated
i n t r a c e l l u l a r f l u x e s of calcium in association w i t h a c t i v a t i o n of RAW 264, as well as the the i n h i b i t i o n of d e v e l o p m e n t of c y t o l y t i c a c t i v i t y by a n t a g o n i s t s of i n t r a c e l l u l a r calcium ( G o r e c k a - T i s e r a et a l . , calcium
may
calmodulin
be
involved
also i n h i b i t
in
the
1986a). A final indication that
activation
process
the i n d u c t i o n of c y t o l y t i c
is
that
activity
by
also
been
inhibitors
of
interferon/LPS
( G o r e c k a - T i s e r a et al. 1986b; Wright et a l . , 1985). Decreased
RNA
synthesis
has
association w i t h macrophage a c t i v a t i o n {Varesio et a l . ,
identified
in
1983, 1984b). A l t h o u g h
the phenomenon has y e t to be i n v e s t i g a t e d w i t h defined r e a g e n t s , it is l i k e l y t h a t the e f f e c t o b s e r v e d is due to the combined action of i n t e r f e r o n and a triggering phenomenon lymphokine
agent
(LPS,
(Varesio, and
LPS
in 1985)
are
these has
studies). shown
characterized
by
that an
Additional
analysis
macrophages imbalanced
of
treated
the with
accumulation
of
mature ribosomal RNA w i t h decreased accumulation of 28S, compared to 18S
153
ribosomal RNA. nor
was
L y m p h o k i n e alone d i d not p r o d u c e a decreased 28/18S r a t i o ,
the
change
found
macrophages.
These f i n d i n g s
alteration
RNA
in
activation, that
metabolism
perhaps
are
in is
to allow
otherwise
held
primed
or
led the a u t h o r one
the
in
inflammatory
(i.e.,
elicited)
to speculate t h a t the o b s e r v e d
that
occurs
late
in
the
process o f
e x p r e s s i o n of e x t a n t c y t o t o x i c c a p a b i l i t i e s
check
until
ribosomal
RNA
metabolism
is
down-regulated. A final and most i m p o r t a n t s u b c e l l u l a r change is the one that confers
on
cells.
macrophages the
The
binding
likely
site
capacity
explanation
on
for
activated
to
distinguish
neoplastic from normal
this phenomenon is the d e v e l o p m e n t o f a
macrophages
that
allows
them
to
interact
p r e f e r e n t i a l l y w i t h neoplastic cells (Marino and Adams, 1980; Piessons, Macrophages inhibited inhibitors Such
activated
with
in t h e i r a b i l i t y that
results
interfered suggest
macrophages
may
recombinant
to kill b y with
that
gamma
interferon
the
LPS
were
70% when t a r g e t cells were t r e a t e d w i t h
oligosaccharide processing binding
recognize
and
1978).
site
that
(Mercurio,
develops
carbohydrates,
on
1986}.
activated
specifically
complex
a s p a r a g i n e - l i n k e d o l i g o s a c c h a r i d e s , on the surfaces o f t u m o r cells. The k i l l i n g
mechanism(s)
used by
a c t i v a t e d macrophages to
kill t u m o r cells may u l t i m a t e l y p r o v e to consist o f multiple e n t i t i e s . One such entity
is the monokine, t u m o r necrosis f a c t o r ( T N F ; Old,
1986).
Gamma
produce
TNF
interferon when
increased
they
were
the
capacity
stimulated by
that
1985; U r b a n et a l . , macrophages had
interleukin
to
2 (Nedwin et a l . ,
1985). 5.2.4
Maintenance of a c t i v a t i o n f o r t u m o r cell kill in~! Once macrophages a r e a c t i v a t e d ,
retain
their
capacity
vitro,
when
removed from a c t i v a t i n g
lose t h e i r a b i l i t y
to
kill
to k i l l .
if
they
are
it
is
essential
that
they
to remain maximally e f f e c t i v e .
stimuli,
In
a c t i v a t e d macrophages q u i c k l y
One cause o f such loss is the n e g a t i v e r e g u l a t o r y
effect t h a t p r o s t a g l a n d i n E 2 has been shown to have on a c t i v a t i o n ( S c h u l t z et a l . , 1978; T a f f e t and Russell, 1981). The o b s e r v a t i o n cultures
contain
a
factor
that
e x p r e s s i o n of c y t o l y t i c a c t i v i t y
that
supernates from stimulated l y m p h o c y t e
prevents
PGE 2 from
( T a f f e t et a l . ,
down-regulating
the
1981) led to the d i s c o v e r y that
the l y m p h o k i n e r e s p o n s i b l e is gamma i n t e r f e r o n (Russell and Pace, 1984b). In l i g h t of t h i s o b s e r v a t i o n , one must t h i n k o f gamma i n t e r f e r o n not only as an activator,
b u t also as a l y m p h o k i n e t h a t maintains c y t o l y t i c a c t i v i t y ,
has been i n d u c e d . activation
Alpha/beta
interferons
in the presence of PGE 2 b u t ,
once i t
also had the c a p a c i t y to maintain
like t h e i r c a p a c i t y to a c t i v a t e ,
they
154
were less e f f i c i e n t than gamma when compared on an a n t i v i r a l basis (Russell and Pace, 198qa). 6.0
CONCLUSIONS D u r i n g the past decade, t h e r e has been a s u b s t a n t i a l increase in what is
known this
a b o u t mononuclear phagocytes and t h e i r brief
summary
interferons,
of
especially
the
recent
functions.
literature
gamma i n t e r f e r o n ,
are
has
critical
It is hoped t h a t
made
clear
that
the
as stimuli t h a t affect
e v e r y t h i n g from the d i f f e r e n t i a t i o n of these cells to the i n d u c t i o n of many of their of
functions.
information
T h e r e is l i t t l e d o u b t that an e q u a l , o r even g r e a t e r amount will
be f o r t h c o m i n g d u r i n g
the n e x t decade.
From this new
body of k n o w l e d g e we will u n d o u b t e d l y develop a c l e a r e r u n d e r s t a n d i n g of how i n t e r f e r o n s i n t e r a c t w i t h o t h e r c y t o k i n e s as p a r t of a n e t w o r k of stimuli that
regulates
the
host
defensive
functions
of
macrophages.
Once
the
r e g u l a t o r y n e t w o r k has been d e f i n e d and the specific mediators have become available,
it
mononuclear may f i n d ,
may
be
possible
to
realize
the
therapeutic
potential
that
phagocytes have a g a i n s t infectious and neoplastic diseases. We
in fact,
t h a t George B e r n a r d Shaw was more c o r r e c t than has been
p r e v i o u s l y t h o u g h t when he had one of his c h a r a c t e r s in the Doctor's Dilemma (1913) exclaim: " T h e r e is at bottom only one g e n u i n e l y scientific t r e a t m e n t f o r all
diseases,
and
that
is
to
stimulate
the
phagocytes.
Stimulate
the
phagocytes." 7.0
LITERATURE CITED
A g u e t , M. and B l a n c h a r d , B . , 1981. High a f f i n i t y b i n d i n g of 1251-labeled mouse i n t e r f e r o n to a specific cell surface r e c e p t o r . I I . A n a l y s i s of b i n d i n g p r o p e r t i e s . V i r o l o g y , 115 : 249-261. A i y e r , R . A , , Serrano, L . E . and Jones, P . P . , 1986. I n t e r f e r o n gamma b i n d s to high and low a f f i n i t y r e c e p t o r components on m u r i n e macrophages. J. I m m u n o l . , 136 : 3329-3334. A n d e r s o n , C . L . and S p e i g e l b e r g , H . L . , 1981. Macrophage r e c e p t o r s f o r IgE: b i n d i n g of IgE to specific I g E Fc r e c e p t o r s on a human macrophage cell line, U-937. J. I m m u n o l . , 126 : 2470-2473. Anderson, P., Yip, Y.K. and V i l c e k , J., 1982. Specific b i n d i n g of 1251-human i n t e r f e r o n gamma to h i g h a f f i n i t y r e c e p t o r s on human f i b r o b l a s t s . J. Biol. C h e m . , 257 : 11,301-11,304. A n d r e w , P.W., Rees, A . D . M . , S c o g i n g , A . , Dobson, N . , Matthews, R . , Whittall, J . T , , Coates, A . R . M . and L o w r i e , B . B . , 1984. Secretion of a m a c r o p h a g e - a c t i v a t i n g f a c t o r d i s t i n c t from i n t e r f e r o n gamma by human T cell clones. E u r . J. I m m u n o l , , 14 : 962-964. A renzana-Seisdedos, F. and Virelizier, J.L., 1983. Interferons as m a c r o p h a g e - a c t i v a t i n c j f a c t o r s . I I . Enhanced secretion of i n t e r l e u k i n 1 by l i p o p o l y s a c c h a r i d e - s t i m u l a t e d human monocytes. E u r . J, I m m u n o l . , 13 : 437-440. A r e n z a n a - S e i s d e d o s , F . , V i r e l i z i e r , J . L . and Fiers, W., 1985. I n t e r f e r o n s as macrophage-activating factors. I I I . P r e f e r e n t i a l effects of i n t e r f e r o n gamma on the i n t e r l e u k i n I s e c r e t o r y p o t e n t i a l of f r e s h o r aged human monocytes. J. I m m u n o l . , 134 : 2444-2448.
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Wietzerbin, J., Gaudelet, C . , Aguet, M. and Falcoff, E., 1986. Binding and cross-linking of recombinant mouse interferon gamma to receptors in mouse leukemic L1210 cells; interferon gamma internalization and receptor down-regulation. J. Immunol., 136 : 2451-2455. Wing, E.J., Waheed, A . , Shadduck, R . K , , Nagle, L.S. and Stephenson, K. , 1982. Effect of colony stimulating factor on murine macrophages. Induction o f a n t i t u m o r a c t i v i t y . J. Clin. Invest., 69 : 270-276. Wisseman, C . L . , Jr. and Waddell, A . , 1983. Interferon-like factors from antigen- and mitogen-stimulated human leukocytes with antirickettsial and cytolytic actions on Rickettsia prowazekii infected human endothelial cells, fibroblasts, and macroph~.~]es. J. i=xp. Med., 157 : 1780-1793. Wong, G.H.W., Clark-Lewis, I . , Harris, A.W. and Schrader, J.W., 1984. Effect of cloned interferon gamma o n expression of H-2 and la antigens on cell lines of hemopoietic, lymphoid, epithelial, fibroblastic and neural o ri g i n : Eur. J. Immunol., lq : 52-56. Wong, G.H.W., Clark-Lewis, I . , McKimm-Breschkin, J . L . , Harris, A.W. and Schrader, J.W., 1983. Interferon gamma induces enhanced expression of la and H-2 antigens on B lymphoid, macrophage and myeloid cell lines. J. Immunol., 131 : 788-793. Wright, B., Zeidman, I. , Greig, R. and Poste, G., 1985. Inhibition of macrophage activation by calcium channel blockers and calmodulin antagonists. Cell. Immunol., 95 : 46-53. Wright, S . D . , Detmers, P . A . , Jong, M . T . C . and Meyer, B . C . , 1986. Interferon gamma depresses binding of ligand by C3b and C3bi receptors on cultured human monocytes, an effect that is reversed by fibronectin. J. Exp. Med., 163 : 1245-1259. Yamamoto-Yamaguchi, Y . , Tomida, M. and Hozumi, M., 1983. Effect of mouse interferon on growth and differentiation of mouse bone marrow cells stimulated by two d i ff e r e n t types of colony stimulating factor. Blood, 62 : 597-601. Yonehara, S., Yonehara-Takahashi, M. and Ishii, A . , 1983. Binding of human interferon alpha to cells of d i ff e r e n t sensitivities: studies with internally radiolabeled interferon retaining full biological a c t i v i t y . J. V i r o l . , 45 : 1168-1171. Yoshie, O., Mellman, I . S . , Broeze, R.J., Garcia-Blanco, M. and Lengyel, P., 1982. Interferon action: effect of mouse alpha and beta interferons on rosette formation, phagocytosis, and surface antigen expression of cells of the macrophage-type line RAW 309Cr.1. Cell. Immunol., 73 : 128-140. Zhang, Z., Fournier, A. and Tan, Y . H . , 1986. The isolation of human beta interferon receptor by wheat germ lectin a f f i n i t y and immunosorbent column chromatographies. J. Biol. Chem., 261 : 8017-8021. Zoon, K . C . , A r n h e i t e r , H., Zur Nedden, D., Fitzgerald, D.J.P. and Willingham, M . C . , 1 9 8 3 . Human interferon alpha enters cells by receptor-mediated endocytosis. Virology, 130 : 195-203. Zoumbos, N . C . , Gascon, P., Djeu, J.Y. and Young, N.S., 1985. Interferon is a mediator of hematopoietic suppression in aplastic anemia in v i t r o and possibly in vivo. Proc. Natl. Acad. Sci. ( U . S . A . ) , 82 : 188-192.
THE
EFFECTS
OF
INTERFERONS
ON
129
MACROPHAGES
AND
THEIR
PRECURSORS STEPHEN W. RUSSELL and JUDITH L . PACE Department of Comparative and Experimental Pathology College o f V e t e r i n a r y Medicine U n i v e r s i t y of F l o r i d a Gainesville, Florida, Supported,
in
32610 U . S . A .
part,
by
research
grants
CA
31199 and
CA
37187 from
the
National C a n c e r I n s t i t u t e . T A B L E OF CONTENTS 1.0
INTRODUCTION
2.0
GENERAL C O N S I D E R A T I O N S
3.0
GROWTH
AND
DIFFERENTIATION
EFFECTS
OF
INTERFERONS
ON
MONONUCLEAR PHAGOCYTES
4.0
3. I
Growth inhibitory effects.
3.2
Growth enhancing effects.
3.3
Differentiating effects.
INFLUENCE OF INTERFERONS ON THE
IMMUNOREGULATORY
ROLES OF
MONONUCLEAR PHAGOCYTES 4.1
Modulation of receptors and surface markers.
4.2
A n t i g e n p r e s e n t a t i o n a n d class [I MHC e x p r e s s i o n .
4.3
Interleukin I secretion.
4.4
Arachidonate
metabolism,
including
prostaglandin
and
leukotriene
s y n t h e s i s and s e c r e t i o n . 5.0
INFLUENCE
OF
INTERFERONS
ON
MONONUCLEAR
PHAGOCYTE
EFFECTOR FUNCTIONS 5.1
C h e m o t a x i s , Fc and C3 r e c e p t o r e x p r e s s i o n , a n d p h a g o c y t o s i s .
5.2
Activation for killing: 5.2.1
M a c r o p h a g e a c t i v a t i n g f a c t o r ( s ) and i n t e r f e r o n s .
5.2.2
Macrophage-mediated microbicidal activity.
5.2.3
Nonspecific killing of tumor cells.
5.2.4
M a i n t e n a n c e of a c t i v a t i o n f o r t u m o r cell k i l l i n g .
5.0
CONCLUSIONS
7.0
L I T E R A T U R E CITED
0165-2427/87/$03.50
© 1987 Elsevier Science Publishers B.V.
130
1.0
INTRODUCTION M a c r o p h a g e s a r e t h e most m a t u r e members o f t h e m o n o n u c l e a r p h a g o c y t e
differentiation regulatory and
series.
This
cell
type
has
a
wide
variety
of
effector
and
f u n c t i o n s t h a t a r e essential to h o s t d e f e n s e a g a i n s t m i c r o o r g a n i s m s
neoplasia.
secretion
of
Many
a
of
their
variety
of
capable in t h i s r e s p e c t t h a t , as much f o r t h e i r p o w e r f u l
protective
soluble
effects
products.
are
In
mediated
fact,
o v e r t h e last decade,
through
macrophages
the
are
so
t h e y h a v e become k n o w n
s e c r e t o r y c a p a c i t i e s as f o r t h e i r more t r a d i t i o n a l ,
phagocytic/scavenger role. M a n y o f the f u n c t i o n s o f m a c r o p h a g e s a r e m o d u l a t e d b y soluble m e d i a t o r s that
are
present
in
their
environment.
macrophages,
themselves;
products
of
T
interferon
is one of t h e most p o t e n t .
lymphocytes,
can be p r o d u c e d too,
can
however,
have
Many
so-called
T
these
are
lymphokines.
Of
The o t h e r i n t e r f e r o n s ,
b y a v a r i e t y o f cell t y p e s , important
of
produced
by
some o f t h e most i m p o r t a n t a r e s e c r e t o r y
regulatory
these,
gamma
alp~ha and b e t a ,
including macrophages. These,
influences.
Some
of
the
effects
that
i n t e r f e r o n s h a v e on m o n o n u c l e a r p h a g o c y t e s h a v e been r e v i e w e d in the r e c e n t p a s t (Basham and M e r i g a n , 1982; Vogel and F r i e d m a n , 1984). Precise
identification
of
the
diverse
i n t e r f e r o n s on macrophages has been d i f f i c u l t .
pharmacologic
actions
of
the
The p r i n c i p a l p r o b l e m has been
u n e q u i v o c a l a s s i g n m e n t of an a c t i v i t y to a g i v e n m e d i a t o r w i t h o u t c o n c e r n t h a t a c o n t a m i n a n t in t h e p r e p a r a t i o n c o u l d e i t h e r be p a r t l y o r w h o l l y r e s p o n s i b l e for the observed effect.
As a r e s u l t o f i m p r o v e d methods o f p u r i f i c a t i o n a n d ,
especially, the introduction
of r e c o m b i n a n t DNA t e c h n o l o g y , such w o r r i e s a r e
now m o s t l y a t h i n g o f the p a s t . T h e w a y s in which the i n t e r f e r o n s a f f e c t the biology
of
mononuclear
because of
this
fact
included
effects
antiviral
effects,
we r e q u i r e d
for
of
phagocytes
that
can now be e v a l u a t e d c r i t i c a l l y .
we u n d e r t o o k the w r i t i n g
interferons
on
mononuclear
that were described prior most t h a t
w e r e used in t h e s t u d i e s .
either
of this r e v i e w . phagocytes,
It
was
We h a v e
other
than
to mid 1986. In selecting p a p e r s
recombinant or highly purified
We r e g r e t if we i n a d v e r t e n t l y
interferons
overlooked anyone's
c o n t r i b u t i o n to t h i s r a p i d l y e x p a n d i n g b o d y o f k n o w l e d g e . 2.0
GENERAL C O N S I D E R A T I O N S T h e r e a r e s e v e r a l k e y c o n c e p t s o f a g e n e r a l n a t u r e t h a t a r e i m p o r t a n t to
understanding gamma
how
interferon
antiviral activity, interferon
will
the is
interferons
more
efficient
affect as a
mononuclear regulatory
t h a n e i t h e r alpha o r beta i n t e r f e r o n . continue
to
prove
more
effective
phagocytes.
molecule,
per
First, unit
of
Whether o r not gamma in
this
regard
when
r e g u l a t o r y a c t i v i t i e s a r e compared on a molar basis remains to be d e t e r m i n e d .
131
Second,
when
the
r e g u l a t o r y "effect
of a m i x t u r e of gamma i n t e r f e r o n
and
e i t h e r alpha o r beta i n t e r f e r o n is compared to t h a t of gamma used alone, the r e s u l t a n t effect is often more Ichan a d d i t i v e . T h i r d , gamma,
can
maintain
characteristics
of
the
expression
mononuclear
the i n t e r f e r o n s , especially
of ~ c e r t a i n
phagocytes
in
functions
the
presence
and
surface
of
negative
r e g u l a t o r y signals. T h e r e are many d i f f e r e n t s u b t y p e s of a l p h a ( l e u k o c y t e ) and at least two k i n d s of beta ( f i b r o b l a s t ) single
species
that
interferon.
is a n t i g e n i c a l l y
Gamma (immune) i n t e r f e r o n occurs as a distinct;
All o f
the i n t e r f e r o n s
interact
w i t h t h e i r t a r g e t cells t h r o u g h surface= r e c e p t o r s . Assuming t h a t t h e r e is l i t t l e difference
in
description
such
is
receptors
offered,
cell t y p e
based
to cell
principally
on
type, what
the f o l l o w i n g general is
known
about
these
s t r u c t u r e s on cells o t h e r than macrophages. It is g e n e r a l l y held t h a t a l p h a / b e t a i n t e f e r o n s share a common r e c e p t o r , while gamma i n t e r f e r o n i n t e r a c t s w i t h one t h a t is separate and d i s t i n c t . This fact is s u p p o r t e d by the r e s u l t s of competition studies ( A g u e t and B l a n c h a r d , 1981; Branca and Baglioni, Joshi et a l . , al.,
1982;
1981; Eppstein et a l . ,
K u s h n a r y o v et a l . ,
1985; Yonehara et a l . ,
1985; Finbloom et a l . ,
1985; Littman et a l . ,
1983; Zhang et a l . ,
1985;
1985; Merlin et
1986), by evidence t h a t the
b i n d i n g site f o r a l p h a / b e t a i n t e r f e r o n is the p r o d u c t of a d i f f e r e n t gene than the one f o r that
show
exposed Gupta,
gamma i n t e r f e r o n that
to
either
1984),
between (1982),
alpha/beta
the
alpha
( R a z i u d d i n et a l . ,
binding
or
beta,
sites but
are
not
receptors
in
when
gamma i n t e r f e r o n
and vice versa ( L i t t m a n et a l . , two
1984) and by e x p e r i m e n t s
internalized
cells
are
(Sarkar
and
1985). T h e r e may be o v e r l a p
some instances,
however.
Anderson
et
al.
f o r example, have shown t h a t human beta i n t e r f e r o n will compete w i t h
gamma i n t e r f e r o n to some e x t e n t f o r b i n d i n g to f i b r o b l a s t s , whereas alpha will not. (3elada et al. ( 1 9 8 4 ) ,
using mouse macrophages d e r i v e d from c u l t u r e s of
bone m a r r o w , have r e p o r t e d similar r e s u l t s , and Zhang et al.
as have Thompson et al.
(1986) u s i n g t h e human l y m p h o b l a s t o i d cell line,
(1985)
Daudi. In
the l a t t e r system, the b i n d i n g of beta could be blocked a p p r o x i m a t e l y 60% b y alpha
and
postulate interferon.
40% b y the In
gamma, causing
existence o f this
two
Thompson
receptors,
and
each of
his colleagues which
would
(1985) bind
to
beta
model, one r e c e p t o r would also b i n d gamma i n t e r f e r o n ,
while the o t h e r would a d d i t i o n a l l y recognize a l p h a . The number of r e c e p t o r s f o r e i t h e r a l p h a / b e t a o r gamma i n t e r f e r o n has g e n e r a l l y been estimated by Scatchard analysis to be f e w e r than 20,000 copies per cell, al.,
r e g a r d l e s s of the cell t y p e
1986; Celada et a l . ,
Langer et
al.,
( A g u e t and B l a n c h a r d ,
1984; Finbloom et a l . ,
1986; Littman et a l . ,
1981; A i y e r et
1985; Hannigan et a l . ,
1985; Merlin et a l . ,
1984;
1985; Weitzerbin et
132
al.,
1986).
The association constants
have r a n g e d from al.,
109M-1 to 1.2 x 108M-1 (Celada et al,
4 x
1985) while dissociation c o n s t a n t s ( K d )
10-11 to al,
(Ka) estimated from such b i n d i n g data
10-9M
1985;
1986;
( A g u e t and B l a n c h a r d ,
Hannigan
et a l . ,
Littman et a l . ,
198~;
1984; Finbloom et
have r a n g e d from a p p r o x i m a t e l y
1981; A i y e r et a l . ,
Kushnaryov
1985; Wietzerbin et a l . ,
et a l . ,
1986; Finbloom et
1985; L a n g e r et a l . ,
1986). C o n t r o v e r s y
still e x i s t s
as to w h e t h e r i n t e r f e r o n r e c e p t o r s e x i s t as homogeneous p o p u l a t i o n s . Of those who maintain t h a t t h e r e is h e t e r o g e n e i t y ( A i y e r et a l . , 1985; Hannigan et a l . ,
1984; O r c h a n s k y et a l . ,
1986; Finbloom et a l . ,
1986; Yonehara et a l . ,
1983),
some have s u g g e s t e d t h a t it is a h i g h a f f i n i t y species of r e c e p t o r t h a t is the b i o l o g i c a l l y r e l e v a n t one. The results of A i y e r et al. (1986) are of p a r t i c u l a r interest
in
the
macrophages
context
and
of
this
review
macrophage
( 5 0 0 / c e l l ) o f high a f f i n i t y
cell
because
lines.
the
They
work
was done using
reported
a
low
number
(Kd = 9.1 x 10-11M) r e c e p t o r s for gamma i n t e r f e r o n
and a l a r g e r number (4,400/ce11) of low a f f i n i t y b i n d i n g sites. Comparison of the r e c e p t o r a f f i n i t i e s and the c o n c e n t r a t i o n o f gamma i n t e r f e r o n needed to induce the e x p r e s s i o n of la and H2 a n t i g e n s led them to conclude that it is the h i g h a f f i n i t y
r e c e p t o r t h a t is b i o l o g i c a l l y r e l e v a n t . As few as 12 b i n d i n g
sites occupied on a steady
state basis were s u f f i c i e n t to cause i n d u c t i o n of
the e f f e c t . Both the N and C terminal p o r t i o n s of mouse gamma i n t e r f e r o n a p p e a r to be i m p o r t a n t f o r b i n d i n g to i t s r e c e p t o r (Russell, J. et a l . , al.
1986). S t r e u l i et
(1981) have also postulated t h a t human alpha i n t e r f e r o n has at least two
regions t h a t are of i m p o r t a n c e in b i n d i n g . The s t r u c t u r e s to which i n t e r f e r o n molecules b i n d on cell surfaces a p p e a r to be asymmetrical p o l y p e p t i d e s ( A g u e t and B l a n c h a r d , Gupta,
1984;
1981;
F a l t y n e k et a l . ,
Thompson
et
al.,
g l y c o p r o t e i n s (Joshi et a l . , Zhang
et
receptors
al.;
1986).
have
been
one
reported
exception
et
1982; L a n g e r et a l . , Wietzerbin
et
al.,
1982; S a r k a r and
al.,
1986)
et
al,,
Zhang
1985),
(Faltynek
1986; Raziuddin et a l . , 1986;
that
1984; Wietzerbin et a l . ,
(Thompson
to e x i s t as single e n t i t i e s
1983; Joshi et a l . , 1984;
Wietzerbin
1982; T r a u b et a l . ,
With
and
Gupta,
1983; Joshi et a l . ,
1985;
et a l . ,
are 1986; the
et a l . ,
1984; S a r k a r
1986)
t h a t have
a p p a r e n t molecular masses r a n g i n g between a p p r o x i m a t e l y 75 and 130 kDa. The r e c e p t o r s can e x i s t on cell surfaces in association w i t h coated pits {Kushnaryov internalized al.,
1984;
et a l . ,
1985;
( A g u e t and Kushnaryov
receptorlligand
complex
( S a r k a r and G u p t a ,
Zoon et a l . ,
Blanchard, et a l . , that
1984).
1981;
1985;
1983).
After
Zoon et a l . ,
is changed
the l i g a n d b i n d s it is
Branca et a l . , little
in
1982; Hannigan et
1983), a p p a r e n t l y as a size a f t e r
it is e n g u l f e d
Isolated nuclei a p p e a r to have r e c e p t o r s f o r beta
i n t e r f e r o n that are of h i g h e r a f f i n i t y
than those on the surface ( K u s h n a r y o v
133
et
al.,
1985).
This
observation
suggests
that
nuclear
binding
of
the
i n t e r f e r o n s may be necessary f o r them to induce t h e i r biological e f f e c t s . Work from
Isaiah F i d l e r ' s
also
suggests
laboratory
that
the
( F i d l e r et a l . ,
intracellular
1985; Saiki and F i d l e r ,
effects
of
interferon
may
1985)
be
most
i m p o r t a n t . Perhaps t h e i r most compelling data in s u p p o r t of this assertion is that
species r e s t r i c t i o n can be a b r o g a t e d i f the surface r e c e p t o r f o r gamma
interferon
is bypassed
( F i d l e r et a l . ,
1985): when the gamma i n t e r f e r o n s of
mouse and man were p r e s e n t e d in liposomes ( w h i c h are r e a d i l y phagocytosed by m a c r o p h a g e s ] , they were e q u a l l y e f f e c t i v e in a c t i v a t i n g the macrophages of either
species,
whereas t h e r e was s t r i c t s p e c i f i c i t y when cells were exposed
to gamma i n t e r f e r o n t h a t was free in the medium. These facts, t o g e t h e r w i t h intimations
from
Branca et a l . ,
other
kinds
of
experiments
1982; Wietzerbin et a l . ,
[Aguet
and
Blanchard,
1981;
1986), s u p p o r t a d e v e l o p i n g consensus
t h a t the i n t e r f e r o n s do not have to be d e g r a d e d a f t e r t h e y are i n t e r n a l i z e d to modulate cell f u n c t i o n . 3.0
GROWTH AND DIFFERENTIATION EFFECTS The i n t e r f e r o n s
regulates progenitor positive
a r e an i m p o r t a n t p a r t o f the n e t w o r k o f mediators t h a t
monocytopoiesis. cell and
in
the
The
bone
negative
mononuclear marrow
under
p h a g o c y t e series arises from a the
growth/differentiation
influence
stimuli,
of
The
a variety
of
differentiation
sequence in the marrow includes the f i r s t i d e n t i f i a b l e cell in this lineage, the monoblast, followed by the p r o m o n o c y t e and then the monocyte. The monocyte is the f i r s t
mononuclear p h a g o c y t e to leave the m a r r o w , so it is also found
n o r m a l l y in the b l o o d . The m a t u r e macrophage o r h i s t i o c y t e d e v e l o p s a f t e r the monocyte e x i t s the c i r c u l a t i o n and e n t e r s the tissues. Macrophages can d i f f e r strikingly
between
body
compartments.
They
are especially
"plastic"
cells,
w i t h many of t h e i r c h a r a c t e r i s t i c s and f u n c t i o n s d e t e r m i n e d by mediators t h a t a r e found in the tissue m i c r o e n v i r o n m e n t . The i n t e r f e r o n s can a f f e c t the g r o w t h of mononuclear phagocytes e i t h e r positively or negatively,
d e p e n d i n g on c o n d i t i o n s . The effects a r e seen e i t h e r
at the level of the p r o g e n i t o r cell in the bone marrow o r ,
to a much lesser
degree,
In a d d i t i o n ,
on
interferons
the can
p r o l i f e r a t i o n o f more d i f f e r e n t i a t e d cause
the
expression
of
forms.
characteristics
and f u n c t i o n s
the that
coincide w i t h the d i f f e r e n t i a t i o n of mononuclear p h a g o c y t e s . 3.1
G r o w t h I n h i b i t o r y Effects o f I n t e r f e r o n s At
the
growth
the level of the bone m a r r o w , the i n t e r f e r o n s n e g a t i v e l y a f f e c t of
a
wide
variety
of
hematopoietic
cell
types.
In
fact,
the
i n t e r f e r o n s may have an i m p o r t a n t role in the pathogenesis of some forms o f
134
aplastic
anemia
(Zoumbos
et
al.,
1985).
which
capacity
are
in
those
vitro
erythrocytes
to
that
yield
(Broxmeyer
limited differentiation
are
pluripotential
macrophages,
et
al.,
potential.
primary
targets
are
1982; Y a m a m o t o - Y a m a g u c h i et al.,
p r o g e n i t o r cells (Hale and M c C a r t h y , among
The
in
nature,
granulocytes,
1983),
as
well
as
i.e.,
early
1983),
with
the
megakaryocytes
those
that
have
or
more
Among t h e l a t t e r g r o u p a r e p r o g e n i t o r s w i t h
the c a p a c i t y to d e v e l o p i n t o e i t h e r macrophages and g r a n u l o c y t e s ( B r o x m e y e r et
al.,
1983;
Klimpel
Yamamoto-Yamaguchi
et
et
al.,
al.,
(Yamamoto-Yamaguchi
et
(Hale
1982) o r
and M c C a r t h y ,
deciding
factor
system.
When
is it
the has
al., kind
been
e f f e c t of t h e i n t e r f e r o n s the
other
1982;
1983)
or,
1983;
Hale
more
Moore and
erythrocytes
of
growth
examined
and
McCarthy,
selectively, Rouse,
macrophages
1983),
granulocytes
(Broxmeyer
stimulus
(Klimpel
that
et a l . ,
is used
et a l . ,
1982;
into
1982),
1983).
The
to d r i v e the
the
inhibitory
has been species specific (as is t h e case f o r most of
b i o l o g i c a l effects
of
the i n t e r f e r o n s ) .
The
inhibitory
p o t e n t i a l of
each of the i n t e r f e r o n s w o u l d , at f i r s t g l a n c e , a p p e a r to be equal ( R a e f s k y et al.,
1985).
However,
the
magnitude
of the effect
on p r o g e n i t o r s
probably
varies depending
on s e v e r a l c o n s i d e r a t i o n s ,
among w h i c h a r e t h e k i n d
and
concentration
colony
(CSF)
For
example,
of
stimulating
Yamamoto-Yamaguchi
containing
predominantly
inhibitory
on
(M-CSF)
compared
interferon
factor al.
(1983)
mouse alpha
progenitor
cells
to
granulocyte/macrophage
et
interferon
stimulated
those
growth
factor
are
employed. that
was more t h a n
with
which
that
ascertained macrophage
had
been
(GM-CSF).
a
mixture
20 times as
growth
factor
stimulated
The
degree
to
with which
is e f f e c t i v e as an i n h i b i t o r o f m a c r o p h a g e c o l o n y f o r m a t i o n a p p e a r s
to be r e l a t e d to the c o n c e n t r a t i o n of CSF t h a t is p r e s e n t in the e n v i r o n m e n t : i n c r e a s i n g t h e c o n c e n t r a t i o n of CSF overcomes t h e i n h i b i t o r y mouse (Klimpel et a l . ,
1982) o r human ( R a e f s k y et a l . ,
e f f e c t of e i t h e r
1985) i n t e r f e r o n s .
A
second v a r i a b l e t h a t i n f l u e n c e s i n h i b i t i o n is t h e t y p e of p r o g e n i t o r cell t h a t is targeted.
T h i s p o i n t was made c l e a r l y in a s t u d y o f human bone m a r r o w cells
conducted alpha,
by
beta
response
of
progenitor susceptible: beta
Broxmeyer and
on
al.
(1983).
interferons
pluripotential
and
Their
have
erythrocyte
results
equal
suggest
ability
progenitor
to
that
human
suppress
cells,
while
the the
t h a t g i v e s rise to g r a n u l o c y t e - m a c r o p h a g e colonies is d i f f e r e n t i a l l y gamma was the most e f f e c t i v e s u p p r e s s o r ,
interferon.
gamma
et
gamma
the
Klimpel et al.
(1983) a g r e e ,
granulocyte-macrophage
m i x t u r e of a l p h a / b e t a i n t e r f e r o n s .
then alpha and, lastly,
placing the inhibitory
progenitor
at
100
times
effect of that
of
a
The i n h i b i t o r y i n f l u e n c e o f a c o m b i n a t i o n o f
gamma and alpha i n t e r f e r o n s was i n c r e a s e d s y n e r g i s t i c a l l y o v e r t h e e f f e c t o f either
one
acting
alone
(Broxmeyer
et
al.,
1985;
Raefsky
et
al.,
1985).
135
A l t h o u g h the evidence was not c o n c l u s i v e , it a p p e a r e d from the r e s u l t s of cell depletion
studies
interferons
were
(Broxmeyer
et a l . ,
mediated d i r e c t l y ,
1983)
not
that
through
inhibitory the
effects
induction
of
the
of mediator
p r o d u c t i o n by mononuclear phagocytes a n d / o r l y m p h o c y t e s t h a t were r e s i d e n t in the bone m a r r o w . The specific mechanism of i n h i b i t i o n may be i r r e v e r s i b l e d o w n - r e g u l a t i o n of e x p r e s s i o n of surface r e c e p t o r s for CSF (Chen, 1986). In a d d i t i o n to p r o m o t i n g the p r o l i f e r a t i o n of bone marrow p r o g e n i t o r cells, at least some CSFs also induce the p r o d u c t i o n of a l p h a / b e t a i n t e r f e r o n s and
prostaglandins
mononuclear
that
phagocytes.
have The
a d h e r e n t bone marrow cells
the
capacity
producers
to
decrease
of these i n h i b i t o r y
(Moore et a l . ,
proliferative
potential
that
was
caused
by
198qb). The r e d u c t i o n
interferon
produced
macrophages was l i k e l y a consequence of induced d i f f e r e n t i a t i o n , i n h i b i t i o n of p r o l i f e r a t i o n alpha/beta being
interferons,
(Moore et a l . ,
prostaglandin
1985).
E (PGE)
Concern
that
in
the
mouse,
by
showing t h a t
obtained
when
C3H/HeJ
mice were exposed
adherent
bone to
by
not d i r e c t
p r o d u c t i o n of
o r all of these mediators was
induced by c o n t a m i n a t i n g e n d o t o x i n , and not by CSF,
least
of
198qa,b), and the effect of each
a p p e a r e d to be mediated i n d e p e n d e n t l y (Moore et a l . , in
production
mediators were
was a l l a y e d , at
similar levels of p r o d u c t i o n could be
marrow CSF.
cells
of
Further,
endotoxin-hyporesponsive, a highly
specific a n t i s e r u m
a g a i n s t CSF also a b r o g a t e d p r o d u c t i o n of both i n t e r f e r o n and PGE (Moore et a l . , 198qb). In a d d i t i o n
to i n t e r f e r i n g
with
the response of p r o g e n i t o r cells in
the m a r r o w , the i n t e r f e r o n s also have a n t i p r o l i f e r a t i v e effects on mononuclear p h a g o c y t e cell lines, e i t h e r the human line, U937 ( H a t t o r i et a l . , et a l . ,
1983) o r the mouse line, J77q.2 {Nagata et a l . ,
1983; Ralph
1984; Schneck et a l . ,
1982). The i n t e r f e r o n used in the s t u d y of U937 was gamma, while i n h i b i t i o n of
proliferation
interferons.
of
J774.2
was
induced
by
a
mixture
of alpha
and
beta
In the l a t t e r case the i n h i b i t o r y e f f e c t was shown by genetic and
biochemical means to be cyclic A M P - d e p e n d e n t . 3.2
G r o w t h Enhancing Effects of the I n t e r f e r o n s While
inhibitory
the
effects,
mononuclear
interferons they
phagocytes
can if
are also
perhaps
best
enhance
the
conditions
are
known
for
proliferative
appropriate.
For
their
growth
capacity
example,
of
when
mouse bone marrow cells were i n c u b a t e d w i t h low c o n c e n t r a t i o n s of a l p h a / b e t a i n t e r f e r o n s , the p r o d u c t i o n of macrophage colonies in response to GM-CSF was s i g n i f i c a n t l y increased, w h i l e the n u m b e r o f colonies p r o d u c e d by M-CSF was inhibited
(Yamamoto-Yamaguchi et
al.,
1983).
Similarly,
response
to
CSF
d e r i v e d from p r e g n a n t mouse u t e r u s was augmented by a m i x t u r e of alpha and
136
beta
interferons,
w h i l e t h e c o m b i n a t i o n o f these same i n t e r f e r o n s
from e n d o t o x i n - s h o c k e d l u n g was i n h i b i t o r y
(Hale and M c C a r t h y ,
with
CSF
1982). Moore
and Rouse (1983) f o u n d t h a t p r e t r e a t m e n t o f mouse m a r r o w w i t h a m i x t u r e o f alpha
and
beta
interferons
caused
macrophage
progenitors
to
retain
their
r e s p o n s i v e n e s s to low c o n c e n t r a t i o n s o f m a c r o p h a g e CSF, w i t h t h e r e s u l t t h a t more
colonies
were
produced
than
without
pretreatment.
Enhancement
was
c l e a r l y d u e to t h e p r o l i f e r a t i o n o f an i n c r e a s e d n u m b e r o f p r o g e n i t o r s and not to a u g m e n t e d p r o l i f e r a t i o n o f the same n u m b e r o f c o l o n y - f o r m i n g cells.
Since
CSF can cause t h e s e c r e t i o n o f i n t e r f e r o n b y cells in t h e bone m a r r o w , Moore and Rouse s p e c u l a t e d t h a t t h e m a g n i t u d e of t h e i n t e r f e r o n marrow dictates interferon)
whether
or inhibited
m o n o c y t o p o i e s i s is a u g m e n t e d (high concentration).
production
in the
(low c o n c e n t r a t i o n o f
These data c o l l e c t i v e l y s u p p o r t
t h e c o n c e p t t h a t t h e c o n c e n t r a t i o n o f i n t e r f e r o n and t h e k i n d of CSF a r e b o t h i m p o r t a n t i f an a u g m e n t e a g r o w t h response o f m a c r o p h a g e p r o g e n i t o r s is to be seen. As an i m p o r t a n t p r a c t i c a l p o i n t ,
the results of
also
of
be
influenced
interferon liquid
and
culture
by
the
GM-CSF but
conditions
stimulated
inhibited
(Yamamoto-Yamaguchi et al., 3.3
the
colony
culture:
formation formation
such e x p e r i m e n t s could
a mixture of
of
in
semisolid
agar
Differentiatinc~ Effects of t h e I n t e r f e r o n s Interferon
1983a).
metamyelocytes
gamma,
but
not
Surprisingly, or
bands
alpha
or
neutrophilic
could
also
undergo monocytic differentiation. Similarly;
gamma
was
the
monocytoid differentiation et a l . ,
culture
1983}.
beta,
caused human c h r o n i c
m y e l o g e n o u s leukemia cells to d i f f e r e n t i a t e to m o n o c y t e - l i k e cells al.,
alpha/beta
m a c r o p h a g e colonies in
be
granulocytes induced
by
as
gamma
mature
as
interferon
to
T h e r e was no e f f e c t on m a t u r e n e u t r o p h i l s .
only
interferon
that
would
cause
in t h e m y e l o m o n o c y t i c human cell l i n e ,
1984; K o e f f l e r et a l . ,
(Perussia et
significant H L - 6 0 (Ball
1984). In a s e p a r a t e i n v e s t i g a t i o n , H a t t o r i et al.
(1983) saw no e v i d e n c e o f d i f f e r e n t i a t i o n o f H L - 6 0 e x p o s e d e i t h e r to alpha o r beta
interferons;
they
did
not
assess
the
effects
of
gamma.
These
same
a u t h o r s d i d see i n d u c t i o n o f m o n o c y t o i d d i f f e r e n t i a t i o n in t h e human cell l i n e , U937,
w h e n i t was e x p o s e d to e i t h e r a l p h a o r beta i n t e r f e r o n .
normal human m o n o c y t e s b y expression
of
morphologic
Becker
(cell v o l u m e ) ,
leucine aminopeptidase) and
functional
i n c r e a s e as m o n o c y t e s m a t u r e . (1985),
working
endogenously by
with
mice,
alpha
In s t u d i e s o f
i n t e r f e r o n d e c r e a s e d the
enzymatic
(phagocytosis)
(acid
phosphatase
markers
that
and
normally
Gamma i n t e r f e r o n also was shown to decrease
the development of phagocytic activity al.
(1984a),
(Becker,
1984b). In c o n t r a s t , Moore et
showed t h a t a l p h a / b e t a i n t e r f e r o n s
mouse bone m a r r o w cells p o s i t i v e l y a f f e c t e d
maturation (phagocytic capability) of progeny macrophages.
produced
the functional
137
4.0
INFLUENCE
OF
INTERFERONS
ON THE IMMUNOREGULATORY
ROLE OF
MACROPHAGES 4. I
M o d u l a t i o n o f R e c e p t o r s and S u r f a c e M a r k e r s The
interferons
affect
the
m a r k e r s on m o n o n u c l e a r p h a g o c y t e s
expression
(Table
I).
of
will summarize w h a t is k n o w n a b o u t these c h a n g e s , class
receptors
and
surface
The r e m a i n d e r o f t h i s section with the exception of the
II MHC a n t i g e n s t h a t a r e c o v e r e d in section 4.2, and t h e r e c e p t o r s t h a t
a r e associated w i t h p h a g o c y t o s i s (Fc and C3; see section 5 . 1 ) . 4.1.1
Fc R e c e p t o r s f o r IgM and 19E The
opsonized with
IgM,
receptor
that
Fc
1969; M a n t o v a n i ,
m a c r o p h a g e s had
least one of t h e
the
portion
interferons
an immune r e s p o n s e .
This
of view,
the
namely,
indicator
IgM
binds
particles
1981). Beta i n t e r f e r o n increased t h e
to b i n d
enhances
IgM (Vogel et a l . , the ability
bind particles that are opsonized with the first
the
of
b u t does n o t n e c e s s a r i l y p r o v i d e t h e signal f o r i n g e s t i o n
( L a y and N u s s e n z w e i g , capacity
for
in
particles
that
1983a). T h u s ,
at
macrophages h a v e to
a n t i b o d y t h a t is p r o d u c e d in
fact is also i m p o r t a n t from a p u r e l y technical p o i n t interpretation
o f complement b i n d i n g
are opsonized with
studies where
IgM and c o m p l e m e n t .
If t h e
IgM
used to f i x complement b i n d s to Fc r e c e p t o r s , t h e n it c a n n o t be d i s t i n g u i s h e d w h e t h e r it is t h e a n t i b o d y o r t h e complement t h a t is r e s p o n s i b l e f o r b i n d i n g ( V o g e l et a l . ,
1983a).
Spiegelberg,
1981)
The cell
to secrete
1982). U937
receptor
human
macrophages
(Anderson
and
because its e n g a g e m e n t induces the
mediators
(Rankin
gamma
interferon
et a l . ,
1982;
R o u z e r et a l . ,
significantly
increased
the
of t h i s r e c e p t o r on t h e s u r f a c e o f t h e human m o n o c y t i c cell l i n e ,
(Naray-Fejes-Toth
homogeneous
by
and
Scatchard
dissociation constant
(Kd).
interferon
same
had
the
Guyre,
is n o t y e t k n o w n ; the
1984).
analysis, As
and
The
receptors
there
was
is so o f t e n t h e case,
magnitude
biological relevance of up-regulation increase
on
important one,
inflammatory
Recombinant
expression
IgE
is an
of
effect
as
no
induced
change
in
were their
n e i t h e r alpha n o r beta gamma
interferon.
The
o f t h e Fc r e c e p t o r f o r IgE b y i n t e r f e r o n
h o w e v e r , one c o u l d s p e c u l a t e t h a t t h i s may be a means to
availability
of
inflammatory
mediators
in
the
locale
of
an
IgE-mediated allergic reaction. 4.1.2
Interleukin 2 (IL-2) receptor Gamma
express
interferon
also
receptors for the lymphokine,
t h e p e r i p h e r a l blood ( H e r r m a n n et a l . ,
induces interleukin
mononuclear
phagocytes
to
2. N e i t h e r m o n o c y t e s from
1985; H o l t e r et a l . ,
1986) n o r cells o f
138
TABLE I Effects of i n t e r f e r o n s on t h e e x p r e s s i o n of s u r f a c e m a r k e r s and r e c e p t o r s on m o n o n u c l e a r p h a g o c y t e s
Receptor or marker
R e g u l a t o r y e f f e c t o f IFN Alpha Beta Gamma
Selected references
Da
B e c k e r et a l . , 1983; E s p a r z a , et a l . , 1986
NK
?
Esparza et a l . , 1986; W r i g h t et a l . , 1986
NK
D
NK
FcR IgG I
U
U
U
Vogel et a l . , 1983a,b; Y o s h i e et a l . , 1982
FcR IgG II
U
U
U
Vogel et a l . , 1983b; Y o s h i e et a l . , 1982
FcR IgM
NK
U
NK
FcR IgE
u
u
U
N a r a y - F e j e s - T o t h and G u y r e , 1984
Class I MHC
U
U
U
K e l l e y et a l . , Wong et a l . , 1984
Class II MHC
?
?
U
B e c k e t , 1984b; K e l l e y et a l . , 1984; Rhodes et a l . , 1983; Sztein et a l . , 1984
NK
NK
D
Hamilton et a l . ,
O
O
U
H e r r m a n n et a l . , 19851 H o l t e r et a l . , 1986
NK
NK
U
K o e s t l e r et a l . ,
Mannosyl, fucosyl terminated g l y c o p r o t e i n s
D
NK
D
Mokoena & G o r d o n , 1985
Lymphocyte function antigen 1 (LFA-I)
O
O
U
S t r a s s m a n n , et a l . , 1985
CR I (C3b)
D
O
CR 3 (C3bi)
NK
Mac-1 ( C 3 b i )
Transferrin Interleukin 2 (IL-2; Tac s u r f a c e a n t i g e n ) A n t i g e n 158.2
Vogel et a l . ,
Vogel e t a l . ,
1983a
1983a
1984; 1983,
a U = s t r o n g l y up r e g u l a t e d ; u = s l i g h t l y up r e g u l a t e d ; D = d o w n r e g u l a t e d ; O = no e f f e c t ; ? = i n c o n s i s t e n t r e s u l t s ; a n d NK = n o t k n o w n .
1984
1985
139
the human monocytic line, U937, o r myelomonocytic line, HL-60 ( H e r r m a n n et
al.,
1985) e x p r e s s IL-2 r e c e p t o r s c o n s t i t u t i v e l y . E x p o s u r e of fresh monocytes
to c u l t u r e c o n d i t i o n s caused a p p r o x i m a t e l y a t h i r d of the population to become positive,
w i t h gamma i n t e r f e r o n causing double t h a t p e r c e n t a g e to e x p r e s s the
receptor
at
monoclonal
twice
the
antibody
number
followed
per by
cell.
Immunoprecipitation
SDS-PAGE
analysis
r e c e p t o r induced on monocytes ( H o l t e r et a l . , al., B
1985) is s t r u c t u r a l l y lymphocytes.
antibody
anti-Tac,
that
2A3),
to
indication
binding
also
bound
anti-Tat that
the
1986) and U937 ( H e r r m a n n et
similar to the one t h a t is found on a c t i v a t e d T and
Further
additional
with
suggested
recognize the
that
studies: the
receptor
it is the same r e c e p t o r comes from
two
IL-2
monoclonal a n t i b o d i e s o t h e r
r e c e p t o r of l y m p h o c y t e s
expressed
by
monocytes.
than
(Tu69 and
Cycloheximide
p r e v e n t e d e x p r e s s i o n of the r e c e p t o r by monocytes stimulated w i t h i n t e r f e r o n , s u g g e s t i n g t h a t de novo s y n t h e s i s is i n v o l v e d r a t h e r than the unmasking of cryptic
r e c e p t o r s . N e i t h e r o f the two g r o u p s r e p o r t i n g this phenomenon found
significantly
increased DNA s y n t h e s i s
stimulated in gamma i n t e r f e r o n - t r e a t e d
mononuclear phagocytes t h a t were exposed to I L - 2 . T h u s ,
it is l i k e l y t h a t the
IL-2 r e c e p t o r is not i n v o l v e d in g r o w t h r e g u l a t i o n of mononuclear p h a g o c y t e s , as it is in l y m p h o c y t e s . Whether engagement of the r e c e p t o r will u l t i m a t e l y be shown to i n f l u e n c e d i f f e r e n t i a t i o n , a f f e c t m a c r o p h a g e / l y m p h o c y t e i n t e r a c t i o n s , o r have some o t h e r i m m u n o r e g u l a t o r y e f f e c t remains to be seen. 4.1.3
T r a n s f e r r i n and mannosyl, fucosyl r e c e p t o r s Macrophages
addition
to
contain,
they
processing
macrophages
also to
effete
have
gamma
(Hamilton et a l . ,
have an
a
integral
erythrocytes surface
interferon
role
and
in
the
iron
metabolism.
hemoglobin
receptor
for
transferrin.
reduced
expression
of
that
they
Exposure this
In of
receptor
1984), a phenomenon t h a t could be mimicked w i t h e i t h e r the
calcium i o n o p h o r e , A23187, o r p h o r b o l m y r i s t a t e acetate (Weiel et a l . , Loss of r e c e p t o r s ,
not decreased a f f i n i t y ,
b i n d i n g of t r a n s f e r r i n .
1985).
was r e s p o n s i b l e f o r the diminished
The p h y s i o l o g i c a l relevance of this o b s e r v a t i o n is, as
yet, unknown. Another lectin-like; fucose
This
monocytes f r e s h l y Exposure
receptor
of
this
is
on
expressed
isolated from the b l o o d , of
the
lymphocytes or interferon expression
receptor
mononuclear
phagocytes
is
i t b i n d s g l y c o p r o t e i n s t h a t are t e r m i n a t e d by e i t h e r mannose o r
residues.
culture.
surface
cells
either
to
to a s l i g h t
d e g r e e by
human
b u t increases w i t h time spent in specifically
challenged,
immune
( e i t h e r alpha o r gamma) r e v e r s i b l y d o w n - r e g u l a t e d
receptor
in
culture
(Mokoena
and
Gordon,
1985).
The
e f f e c t could be p r e v e n t e d by the a n t i i n f l a m m a t o r y s t e r o i d , dexamethasone. In
140
c o n t r a s t to w h a t is g e n e r a l l y f o u n d , any,
in this human system t h e r e was l i t t l e , if
d i f f e r e n c e between the effects of alpha and gamma i n t e r f e r o n s .
other
hand,
only
gamma i n t e r f e r o n
On the
had the c a p a c i t y to d o w n - r e g u l a t e this
r e c e p t o r on mouse macrophages. 4.1.4
L y m p h o c y t e f u n c t i o n anti~len 1 and antic=len 158.2 These
(Strassmann
et
quiescent,
al.,
antigens 1985,
peritoneal
(inflammatory) that
stimulated
LFA-1 by
macrophages
marked
activating
thioglycollate, exposing
but
them
either
stimulate e x p r e s s i o n . However, one
must
interferons
lack
activity,
They
then
In
kinds
of
i.e., elicited
were e i t h e r
vitro,
LFA-1
Thus,
it would
partially or
could
be
fully
induced
on
e l i c i t e d p e r i t o n e a l macrophages by or
bacterial
lipopolysaccharide.
at the c o n c e n t r a t i o n s used, were able to
judgment
because by
Some
LFA-1
resident,
in view of the a b i l i t y t h a t LPS had to induce
reserve
phagocytes
markers.
by
b u t macrophages t h a t were e i t h e r
gamma i n t e r f e r o n
expression,
macrophages.
mice.
macrophages t h a t
agents.
as
expressed
e x p r e s s e d the a n t i g e n .
not proteose p e p t o n e ,
to
primarily
not of
killing
N e i t h e r alpha n o r beta i n t e r f e r o n s ,
mononuclear
used is
macrophages were p o s i t i v e ,
primed or fully activated for appear
are
1986)
as
LPS
stimulating
to
whether
mediates
many
secretion
of
or
not
alpha/beta
of
its
effects
on
interferons
by
these
feed back on the cells t h a t p r o d u c e d
them in an
a u t o c r i n e manner. A d d i t i o n a l studies are needed w i t h h i g h e r c o n c e n t r a t i o n s of exogenous alpha and beta i n t e r f e r o n s to e n s u r e t h a t they are not simply less e f f i c i e n t than gamma at i n d u c i n g e x p r e s s i o n of L F A - 1 . The e x p r e s s i o n of a n t i g e n also
up-regulated
macrophages t h a t
by
gamma
158.2
interferon.
were primed for
( K o e s t l e r et a l . ,
Its
expression
t u m o r cell k i l l i n g ,
i.e.,
1985)
increased
is on
changed to the
e x t e n t that they could be t r i g g e r e d to develop c y t o l y t i c a c t i v i t y by v e r y small amounts of a second, t r i g g e r i n g that
they
were
tumoricidal.
signal (such as LPS),
Treated
ingested L i s t e r i a monocyto~enes.
cells
b u t not to the e x t e n t
were m i c r o b i c i d a l ,
Like L F A - 1 ,
however,
for
the e x p r e s s i o n of this antigen
was also increased a f t e r macrophages were exposed to LPS, b u t not to e i t h e r alpha
or
beta
interferons.
Caution
is
needed
again
here,
however,
in
i n t e r p r e t i n g r e s u l t s , as the c o n c e n t r a t i o n of a l p h a / b e t a i n t e r f e r o n s used was only
100 times t h a t of gamma (based on a n t i v i r a l u n i t s ) .
500 to
1,000 times more alpha
or
beta
interferon
i m m u n o r e g u l a t o r y potential of gamma i n t e r f e r o n .
In many instances,
is needed
to mimic the
141
4.2
Anticjen Presentation and Class II MHC Expression For
efficient
development of
immune responses,
antigen
p r e s e n t e d to l y m p h o c y t e s b y a n t i g e n p r e s e n t i n g cells ( A P C } , class
II MHC gene p r o d u c t s .
class
II
antigens
positioned
at
C e r t a i n APC,
constitutively.
portals
of
entry,
be
such as d e n d r i t i c cells, e x p r e s s
Generally,
antigen
must
in c o n c e r t w i t h
such
are
cells
sessile,
are
and
relatively they
are
few, poorly
p h a g o c y t i c . Mononuclear p h a g o c y t e s g e n e r a l l y do not e x p r e s s class II a n t i g e n s unless t h e y
have been a p p r o p r i a t e l y
stimulated to do so. They c o n s t i t u t e a
h i g h l y mobile pool o f a v i d l y p h a g o c y t i c cells t h a t can be marshalled r a p i d l y at a site.
Thus,
one m i g h t view mononuclear phagocytes as a r e s e r v e that is
mobilized to augment and APC
a m p l i f y immune responses which a r e i n i t i a t e d by
r e s i d e n t at a site of a n t i g e n i n c u r s i o n .
phagocytes
provide
ability
process,
to
increased i.e.,
p a r t i c u l a t e material t h a t value,
however,
numbers
ingest,
of
the
cells
cells,
degrade
they encounter.
unless
Not only do these mononuclear they
and
also c o n t r i b u t e
present
to
the
lymphocytes
Such a r e s e r v e would be of l i t t l e
that
constitute
it
could
be i n d u c e d
to
e x p r e s s class II a n t i g e n s . From the many c i t a t i o n s t h a t that
gamma i n t e r f e r o n
mononuclear number
cells
expression Papiernik
per et
After
expressing cell
al.,
the conclusion is inescapable
induces the e x p r e s s i o n of class
phagocytes.
of
follow,
were
class
II
increased
1986).
1,25-dihydroxyvitamin
exposure
(Becker,
et
gamma
antigens
Expression
D 3 (Morel
to
was
al.,
and
II MHC a n t i g e n s on interferon,
the
1985;
Cershon
enhanced
1986).
density
by
While
et
the
both
the
of a n t i g e n al.,
1985;
presence
most w o r k e r s
of
would
s u p p o r t the notion of a d i r e c t e f f e c t b y gamma i n t e r f e r o n on its t a r g e t cells, there
is one r e p o r t (Walker et a l . ,
1984) o f gamma i n t e r f e r o n also a c t i n g to
e l i c i t the release of a class I I - i n d u c i n g f a c t o r t h a t n e i t h e r induces a n t i v i r a l activity
nor
blocks
the
class
II-inducing
effects
of
gamma
interferon.
Messenger RNA specific for class II p o l y p e p t i d e s could be d e m o n s t r a t e d in the cells of mononuclear p h a g o c y t e lines of both human b e i n g s (HL-60; K o e f f l e r et al.,
1984)
and mice (P388D1;
treated
with
gamma
adults,
fetal
(Kelley et a l . ,
monocytes
would
also
mononuclear
phagocytes
antigens
culture
in
Sztein
et
al.,
In
addition
1984) a f t e r
they
mononuclear
to gamma i n t e r f e r o n
by
had been
phagocytes
of
1984) human
d e v e l o p i n g class
II
A similar effect could be o b s e r v e d when p u r i f i e d
were allowed
and
to
1984) and neonatal (Stiehm et a l . ,
respond
a n t i g e n s on t h e i r s u r f a c e s .
1984;
Nakamura et a l . ,
interferon.
were
1984).
then Such
antigen presenting capabilities with
to
lose t h e i r
treated cultured
complement of
w i t h gamma i n t e r f e r o n cells
concomitantly
class
II
(Belier,
reacquired
new class II a n t i g e n e x p r e s s i o n ( B e l i e r ,
198q}. I m p l i c i t in the r e s u l t s o f these l a t t e r s t u d i e s , and those of Steeg et al.
142
(1982b),
is
the
fact
phagocytes cannot
that
expression
of class
be maintained w i t h o u t
II
antigen
continuous
by
mononuclear
stimulation by
gamma,
and p e r h a p s o t h e r k i n d s of i n t e r f e r o n . Whether expression
or
o f class
not
alpha
and
beta
interferons
also
induce
q u e s t i o n . T h e r e are clear r e p o r t s of t h e i r ineffectiveness (Ball et a l . , Becket, 1984;
1984b; Kelley et a l . , Vogel
et
unequivocal 1983;
al.,
class
1984; P a p i e r n i k et a l . ,
1983a);
however,
I I-inducing
Sztein et a l . ,
different
1984).
inductive
activity
applicable
efficiencies,
potentials
was
for
reduced,
alpha
and
at
least
to alpha
rather
1984;
1986; V i r e l i z i e r et a l . , two
studies
interferon
The a p p a r e n t d i s c r e p a n c y
the a l p h a / b e t a and gamma i n t e r f e r o n s . is
the
II a n t i g e n s on mononuclear phagocytes is still an open
do
ascribe
(Rhodes
et
al.,
may again be due to
than an absolute d i f f e r e n c e
between
The likelihood t h a t such an a r g u m e n t
however,
by
the
gamma i n t e r f e r o n s
finding
of
similar
inductive
when the two i n t e r f e r o n s
were
d i r e c t l y compared in the same series of e x p e r i m e n t s (Sztein et a l . , 1984). Numerous
agents
will
interfere
with
the
capacity
of
gamma
i n t e r f e r o n to induce class II a n t i g e n e x p r e s s i o n . An a p p a r e n t p a r a d o x is the fact
that,
antigens
while (Rhodes
alpha/beta et a l . ,
interferons
1983;
caused
Sztein et a l . ,
the
expression
1984),
they
of class
interferon~s a b i l i t y to induce these surface a n t i g e n s ( l n a b a et a l . , et a l . ,
inhibitors
et
al.,
antibody Vogel,
1986; Ling
1985). Such i n h i b i t i o n was a p p a r e n t l y not mediated by p r o s t a g l a n d i n s ,
because (Ling
II
i n h i b i t e d gamma
of
the
1985).
specific
cyclooxygenase
Instead,
for
the
alpha/beta
synthetic
inhibitory
interferons.
pathway
effect
could
had be
Glucocorticoids
1985b) and immune complexes ( V i r g i n et a l . ,
no effect
blocked (Warren
by and
1985) were also e f f e c t i v e
i n h i b i t o r s of class II a n t i g e n e x p r e s s i o n by gamma i n t e r f e r o n , the l a t t e r only if the Fc p o r t i o n of the a n t i b o d y molecule was i n t a c t . Complexes composed of IgG1,
IgG2a,
IgG2b and
IgM o r IgA were not. 1982a),
dibutryl
interferon.
Endotoxin
macrophages prostaglandin
to
but
those c o n s i s t i n g of e i t h e r
P r o s t a g l a n d i n E 2 (Gershon et a l . ,
cAMP
1982a) also i n h i b i t e d
IgE were e f f e c t i v e , (Steeg
,~.t a l . ,
the i n d u c t i o n of class undoubtedly
secrete
synsthesis,
PGE 2,
the
(Steeg et a l . ,
II a n t i g e n e x p r e s s i o n by gamma
mediated
because
reversed
1985; Steeg et a l . ,
1982a) and e n d o t o x i n its
effects
indomethacin, inhibitory
by an
effect
in
stimulating inhibitor
of
experiments
p e r f o r m e d by Steeg and h e r colleagues (1982a). The
interferons
were also able to
class I MHC a n t i g e n s (Kelley et a l . , 1983, 1984; Yoshie et a l . ,
1982).
up-regulate
the e x p r e s s i o n of
1984; K i n g and Jones, 1983; Wong et a l . ,
In c o n t r a s t to class II MHC a n t i g e n s , those
of class I were induced on a v a r i e t y of cell t y p e s by a n y of the t h r e e classes of i n t e r f e r o n
(Kelley et a l . ,
1984).
Expression was e n g e n d e r e d on cells
in
143
vivo,
as
well
as
Rhodes et a l . , antigen
of
regulated antigens
vitro
on
different
these
two
et a l . ,
independently
cell
classes (Wong
Nakamura et a l . ,
1984;
1985). Dissociation of class I and II
types of
et
1986;
suggested
major
al.,
that
interferon
histocompatibility
1984).
The
finding
driven
antigen that
was
class
II
were induced by gamma i n t e r f e r o n p r i m a r i l y on cells of the immune
system ( K i n g and Jones, this
(Momburg
1983; Skoskiewicz et a l . ,
induction
expression
in
1983; Wong et a l . ,
1983,
1984) was c o n s i s t e n t w i t h
l y m p h o k i n e ' s known c a p a c i t y to enhance immunologic responses ( B e c k e r ,
1985; Nakamura et a l . , 4.3
1984; Sztein et a l . , 198q).
Maintenance and
Enhancement of
Interleukin
1 (IL-1)
Secretion by
Interferons Another through study
their
way
effect
(Boraschi
et
that
on al.,
interferons
IL-1
can
secretion
1984),
affect
the
immune response is
by mononuclear p h a g o c y t e s .
gamma
but
not
alpha
interferon
In one directly
stimulated the p r o d u c t i o n o f IL-1 by mouse r e s i d e n t p e r i t o n e a l macrophages. In a n o t h e r instance ( A r e n z a n a - S e i s d e d o s and V i r e l i z i e r , alone
were
interferons
not
able
to
stimulate
secretion;
had an e n h a n c i n g e f f e c t .
Again
most efficacious of the t h r e e t y p e s .
1983), the i n t e r f e r o n s
however,
here,
The a b i l i t y
any
one
of
the
gamma i n t e r f e r o n was the to secrete
IL-1
is lost by
mononuclear phagocytes when t h e y are maintained in c u l t u r e . The i n t e r f e r o n s , particularly
gamma,
have
the
capacity
to
maintain
such s e c r e t o r y c a p a c i t y
( A r e n z a n a - S e i s d e d o s et a l . , 1985; Haq et a l . ; 1985). 4,4
Arachidonate
Metabolism,
Includin~l
Prostaglandin
and
Leukotriene
Synthesis and Secretion The p r o d u c t s of a r a c h i d o n i c acid metabolism are i m p o r t a n t both as immunoregulatory
and
inflammatory
mediators.
Thus,
by
influencing
the
secretion of these metabolites, the i n t e r f e r o n s influence both the immune and i n f l a m m a t o r y responses. As w i t h I L - 1 , mononuclear
phagocytes
to
none of the i n t e r f e r o n s alone induced
secrete
either
cyclooxygenase/lipoxygenase metabolites. significantly
enhance
secretion
d i e s t e r s (Boraschi et a l . ,
induced
arachidonic
However, by
some
1985; Hamilton et a l . ,
acid
gamma stimuli,
or
its
interferon
did
notably
phorbol
1985). Whether secretion that
is caused b y o t h e r s t i m u l i , such as zyrnosan, insoluble immune complexes o r the calcium ionophore, A23187, due to c o n f l i c t i n g and
his
results
colleagues
is a l t e r e d b y the i n t e r f e r o n s is still u n c l e a r ,
reported
(1985)
in the l i t e r a t u r e .
reported
that
secretion
For example, Hamilton of
arachidonic
acid
metabolites from e l i c i t e d mouse p e r i t o n e a l macrophages p r e t r e a t e d w i t h gamma interferon
and
then
stimulated
with
the
calcium
ionophore,
A23187,
was
144
unaltered.
In
pretreatment
apparent of
direct
resident,
contrast,
i.e.,
Boraschi
unstimulated,
et
al.
(1985)
found
that
mouse peritoneal macrophages
w i t h gamma i n t e r f e r o n i n h i b i t e d a r a c h i d o n i c acid and l e u k o t r i e n e C 4 release by A23187,
but
greatly
increased the release of the c y c l o o x y g e n a s e p r o d u c t s ,
PGE 2 and 6 - k e t o PGF 1 a l p h a . The two g r o u p s d i f f e r e d s i m i l a r l y w i t h r e g a r d to release
stimulated
pretreated
with
decrease,
while
evaluation
of
macrophages
gamma
interferon:
Hamilton
the
metabolism by
from
and
effects
his
of
by
zymosan
Boraschi
and
associates
alpha/beta
after her
found
had
colleagues no
interferons
they effect.
on
been
noted
a
The
only
arachidonic
acid
macrophages has been made by Boraschi et al.
(1984,
1985).
P r e t r e a t m e n t of the cells w i t h alpha o r beta i n t e r f e r o n s d r a m a t i c a l l y decreased arachidonic
acid
liberation
from
membrane
phospholipids,
as
well
as
the
formation of c y c l o o x y g e n a s e and l i p o x y g e n a s e p r o d u c t s , a f t e r s t i m u l a t i o n . 5.0
INFLUENCE
OF
INTERFERONS
ON
MONONUCLEAR
PHAGOCYTE
EFFECTOR FUNCTIONS 5.1
Chemotaxis, Fc and C3 Receptor E x p r e s s i o n , and Phacjocytosis Macrophages
differentiate
in
inflammatory
reactions
predominantly
from monocytes t h a t are mobilized from the blood. Once monocytes leave the v a s c u l a r system, they c r a w l along stromal elements, such as collagen f i b e r s , following
a
gradient
of
chemotactic
stimuli
that
diffuse
out
from
the
inflammatory s i t e . Alpha i n t e r f e r o n has been shown to decrease both random (chemokinetic) and d i r e c t e d (chemotactic) m i g r a t i o n of monocytes (Ohmann and Babiuk,
1984). Whether o r not this has a n y t h i n g to do w i t h i n t e r f e r o n acting
as m i g r a t i o n i n h i b i t o r y
factor
both alpha ( T h u r m a n et a l . , et a l . ,
1984) i n t e r f e r o n s ,
(MIF),
an a c t i v i t y
t h a t has been a s c r i b e d to
1985) and gamma ( T h u r m a n et a l . ,
1985, Varesio
is a question t h a t needs f u r t h e r e x p l o r a t i o n . In its
M I F - l i k e role; gamma was more p o t e n t than alpha i n t e r f e r o n ( T h u r m a n et a l . , 1985). Beta i n t e r f e r o n increased s p r e a d i n g p r o p e r t i e s of macrophages (Rollag and Degre, 1982). Once
at
p h a g o c y t i c cells
the
site of
inflammation,
one of
is e n g u l f m e n t of p a r t i c u l a t e m a t e r i a l .
removal of d e b r i s and f o r e i t h e r be opsonized o r not.
the
main
k i l l i n g of ingested m i c r o o r g a n i s m s . Degre and
Rollag (1982)
functions
of
The need is both f o r Particles can
have shown t h a t beta
i n t e r f e r o n will stimulate the u p t a k e of unopsonized Escherichia coil b a c t e r i a by mouse
peritoneal
Staphylococcus bovine
monocytes
B a b i u k , 1984).
macrophages.
aureus and
bacteria
Phagocytosis was similarly
macrophages
with
of
opsonized
stimulated by
alpha
interferon
E.
coli
and
p r e t r e a t m e n t of (Ohmann
and
145
The opsonins t h a t p r i n c i p a l l y mediate u p t a k e of p a r t i c u l a t e material by
mononuclear phagocytes are a n t i b o d y and cleavage p r o d u c t s of the t h i r d
component of complement. Two complement r e c e p t o r s have been examined w i t h r e g a r d to the effects t h a t i n t e r f e r o n s have on them: CR I (C3b r e c e p t o r ) and CR III
(C3bi r e c e p t o r ) .
mononuclear
phagocytes
phagocytes
to
(Becket
al.,
et
The Mac-1 epitope is on the C3bi r e c e p t o r of mouse (Belier
interferon 1983
et
al.,
either
[alpha
[ g a m m a ] ; Wright et a l . , [beta];
has
or
1982).
caused
Exposure
reduced
gamma i n t e r f e r o n s ] ;
1985a [ a l p h a / b e t a ] ;
mononuclear of
CR
Esparza et a l . ,
1986 [ g a m m a ] ) and CR I l l / M a c - 1
Warren and V o g e l ,
of
expression
(Vogel et a l . ,
Wright et a l . ,
I
1986 1983a
1986 [gamma])
o r has had no d e t e c t a b l e e f f e c t on the e x p r e s s i o n of these r e c e p t o r s ( B e c k e t et a l . , al.,
1983 [ b e t a
interferon];
1986 [ g a m m a ] ) .
Esparza et a l . ,
1986 [ g a m m a ] ;
P a p i e r n i k et
The s u g g e s t i o n has been made that reduced b i n d i n g to
CR I is not due to i n t e r n a l i z a t i o n of the r e c e p t o r (Esparza et a l . ,
1986). The
a u t h o r s based this conclusion on t h e i r f i n d i n g that both plasma membrane and i n t r a c e l l u l a r pools of r e c e p t o r decreased a f t e r t r e a t m e n t w i t h i n t e r f e r o n . This interpretation
should
be
revisited,
however,
because c o n s i d e r a t i o n
was not
g i v e n to the p o s s i b i l i t y t h a t r e c e p t o r could have been d e g r a d e d a f t e r it was i n t e r n a l i z e d . Whatever the cause of the reduced b i n d i n g , within
it can be r e v e r s e d
45 minutes by a l l o w i n g macrophages to spread on a surface coated w i t h
f i b r o n e c t i n ( W r i g h t et a l . , 1986). In c o n t r a s t to the s u p p r e s s i v e effect t h a t i n t e r f e r o n s g e n e r a l l y have on the b i n d i n g of complement components, the general f i n d i n g has been that i n t e r f e r o n t r e a t m e n t increases Fc-mediated b i n d i n g of a n t i b o d y to mononuclear phagocytes ( B e c k e t et a l . , Perussia et a l . , 1983b;
Wang
complete
1983; Esparza et a l . ,
1983b; Ralph et al,
et
al.,
concurrence,
1984; the
1986; C u y r e et a l . ,
1983; Rhodes et a l . ,
Yoshie
et
al.,
phenomenon
1982).
appears
increased e x p r e s s i o n of the r e c e p t o r s ( G u y r e et a l . , 1983b; Vogel et a l . , RNA
and
protein
disagreement with
1983b; Yoshie et a l . , synthesis
(Yoshie
this conclusion
et
1983; Vogel et a l . ,
Although
most
1983 ;
likely
there to
is
not
be due
to
1983 ; Perussia et a l . ,
1982), which depends on c o n t i n u e d al.,
1982).
(Wang et a l . ,
The
one
report
in
1984) d e s c r i b e d no increase
when FcR II r e c e p t o r e x p r e s s i o n was q u a n t i f i e d using the Fab f r a g m e n t of an a n t i - r e c e p t o r monoclonal a n t i b o d y .
When it has been measured, no change in
Fc
been found
receptor
binding
( G u y r e et a l . ,
affinity
has
1983 ; Perussia et a l . ,
following
interferon
treatment
1983b). U p - r e g u l a t i o n of Fc r e c e p t o r s
by the i n t e r f e r o n s seems to be b r o a d l y applicable to myeloid cells, e . g . , mature n e u t r o p h i l s can be a f f e c t e d p o s i t i v e l y (Perussia et a l . , same s t u d y ,
even
1983b). In the
t h e r e was no d e t e c t a b l e effect on the e x p r e s s i o n of Fc r e c e p t o r s
by neoplastic cells of l y m p h o i d lineage.
146
As one m i g h t e x p e c t , changes in the e x p r e s s i o n of r e c e p t o r s on the surfaces of mononuclear phagocytes a l t e r the p h a g o c y t i c c a p a b i l i t i e s of these cells.
Uptake
1984a,b;
of
zymosan
Becker
et a l . ,
is
decreased
1983).
Whether
by
interferon
this
phenomenon is a t t r i b u t a b l e to
treatment
reduced e x p r e s s i o n / f u n c t i o n of the complement r e c e p t o r s ,
(Becker,
to a r e d u c t i o n in
e x p r e s s i o n of the mannosyl, fucosyl r e c e p t o r (Mokoena and G o r d o n , both,
is not k n o w n .
r e c e p t o r s on i n t e r f e r o n - t r e a t e d
macrophages,
ingestion d i d not ensue unless
t h e r e was f u r t h e r stimulation of the cells, e . g . , (Wright
et
al.,
greatly
enhanced
endogenously
1985), or
Even when b i n d i n g c a p a b i l i t y is r e s t o r e d to complement
1986). by
Fc-mediated interferon
produced
by one of the phobol d i e s t e r s
phagocytosis,
treatment.
alpha/beta
As
on
the
other
mentioned
interferons
may
in
be
hand,
section
critical
is 3.3,
to
the
development of Fc r e c e p t o r - m e d i a t e d p h a g o c y t i c c a p a b i l i t i e s b y d i f f e r e n t i a t i n g mononuclear phagocytes (Moore et a l . ,
1985; Vogel and F e r t s c h ,
1984). Once
macrophages have developed such a c a p a b i l i t y , the role of the i n t e r f e r o n s may be
to
enhance
this
important
inflammatory r e a c t i o n .
host
defense
In one s t u d y ,
both
mechanism at
the
site
the rate of p h a g o c y t o s i s and the
total u p t a k e of p a r t i c l e s by macrophages were increased (Wang et a l . , All
three
interferon
types
have
been
of an
effective,
although
1984).
gamma i n t e r f e r o n
again seems to be the most e f f e c t i v e . Both the FcR I and FcR II r e c e p t o r s f o r mouse
IgG
were
affected
(Vogel
et
al.,
1983b).
The
enhancement of
Fc
r e c e p t o r - m e d i a t e d phagocytosis by gamma i n t e r f e r o n was increased even more by
the a d d i t i o n of c o r t i c o s t e r o i d s (Warren and V o g e l ,
1985b). The effect on
Fc r e c e p t o r - m e d i a t e d p h a g o c y t o s i s seemed to be r e g u l a t e d s e p a r a t e l y from t h a t of
the
antiviral,
interferons
antiproliferative
( F e r t s c h and Vogel,
m i c r o t u b u l e s and
and
these
findings,
activating
1984; Vogel et a l . ,
activities
of
the
1986). U l t r a s t r u c t u r a l l y ,
10 nm filaments a g g r e g a t e d in the p e r i n u c l e a r cytoplasm of
macrophges t r e a t e d w i t h beta i n t e r f e r o n , of
NK
elements
beneath
the
in association w i t h r e l a t i v e c l e a r i n g
plasmalemma
together with other indicators,
(Wang
et
al.,
1984).
These
led Wang and colleagues to conclude
t h a t enhancement of Fc r e c e p t o r - m e d i a t e d p h a g o c y t o s i s was due to accelerated association of actin filaments w i t h the plasma membrane d u r i n g the e n g u l f m e n t of p a r t i c l e s . 5.2
Activation for killing 5.2. I
Macrophage a c t i v a t i n g f a c t o r ( s ) and i n t e r f e r o n s The
morphologically macrophages
by
from
activated
state
in
macrophages
was
George Mackaness while he was w o r k i n g mice
infected
with
Listeria
first
recognized
with
monocytogenes
peritoneal
(Mackaness,
147
1962).
He
noted
subsequently
immunologically
specific
caused
rapid
a more
that
induction
of
the
activated
state
is
(second e x p o s u r e of a mouse to the same organism onset
of
activation,
and
t h i s c h a r a c t e r i s t i c could be
t r a n s f e r r e d a d o p t i v e l y to a naive mouse w i t h immune l y m p h o c y t e s ) ; that once macrophages were a c t i v a t e d they c o n f e r r e d p r o t e c t i o n n o n s p e c i f i c a l l y against a range of a n t i g e n i c a l l y u n r e l a t e d p a t h o g e n s ; and he speculated t h a t a c t i v a t i o n was
induced
1969;
Miki
by
a secretory
and
Mackaness,
product(s) 1964).
of
As
lymphocytes
will
be
seen
(Mackaness,
in
the
1964,
following
two
sections, Mackaness ~ f i n d i n g s have been e x t e n d e d and r e f i n e d d u r i n g the past twenty years.
However,
his
initial c o n t r i b u t i o n s are remembered as some of
the most i m p o r t a n t and seminal in the f i e l d . The soluble p r o d u c t of l y m p h o c y t e s a b o u t which Mackaness speculated factor,
was
later
identified
and
o r MAF (Piessens et a l . ,
given working
MAF would not a c t i v a t e macrophages f o r signal
(Weinberg
et
Weinberg
(endotoxin,
al.,
et al.
1978).
name macrophage a c t i v a t i n g
1975). A few y e a r s l a t e r ,
Brice Weinberq and his colleagues, triggering
the
in
their
However,
it
it was shown by
in John Hibbs ~ l a b o r a t o r y , t h a t
t u m o r cell k i l l i n g unless a second, case)
was
is now
present
known
that
in
the
the
medium
f i n d i n g s of
do not a p p l y e q u a l l y to all k i n d s of m a c r o p h a g e - m e d i a t e d ,
nonspecific k i l l i n g because t a r g e t s and the levels of a c t i v a t i o n needed to deal with
them a p p a r e n t l y d i f f e r .
One must s p e c i f y ,
therefore,
the p u r p o s e for
which a macrophage is a c t i v a t e d when the term is used, e . g . ,
activation for
t u m o r cell k i l l i n g o r f o r l i s t e r i a c i d a l a c t i v i t y . A
major advance
in
the
field
was the
d e m o n s t r a t i o n in a
l a r g e n u m b e r of l a b o r a t o r i e s d u r i n g 1982-83 that one, i f not the main, form o f MAF is gamma i n t e r f e r o n M u r r a y et a l . , 1983a,b; 1983;
( K l e i n s c h m i d t and S c h u l t z ,
1983; Nathan et a l . ,
Roberts and V a s i l ,
Schultz
and
1982;
1983; O r t a l d o et a l . ,
1982; Rothermel et a l . ,
Kleinschmidt,
Le et a l . ,
1983;
1983; Pace et a l . ,
1983; S c h r e i b e r et a l . ,
1983; Wisseman and Waddell,
1983).
These
i n i t i a l r e p o r t s have since been c o n f i r m e d and e x t e n d e d b y a d d i t i o n a l in v i t r o (Le and V i l c e k , et a l . ,
1984; Ockenhouse et a l . ,
1985; S p i t a l n y and Havell,
Winkler,
1984; U t s u g i and Sone,
(Buchmeier and S c h r e i b e r , studies.
In r e t r o s p e c t ,
1984; Passwell et a l . ,
1984; S v e d e r s k y et a l . ,
1986; and Varesio et a l . ,
1985; K i d e r l e n et a l . ,
1986; Sadlik
1984; T u r c o and 1984a) and in v i v o
1984; M u r r a y et a l . ,
1985)
it should not have been s u r p r i s i n g to d i s c o v e r in the
1980s t h a t at least one k i n d of MAF and i n t e r f e r o n
are the same: Richard
Schultz,
had
working
in
Michael
Chirigos ~ laboratory,
already
published
several p a p e r s in the late 1970s t h a t showed s i m i l a r i t i e s between macrophage activating Schultz
f a c t o r and c r u d e p r e p a r a t i o n s of i n t e r f e r o n and
Chirigos,
1978,
1979).
Before
this,
(Schultz et a l . ,
Samuel
Salvin
and
1977; his
148
colleagues had shown t h a t mice w i t h d e l a y e d - t y p e h y p e r s e n s i t i v i t y reactions had both
interferon
and m i g r a t i o n i n h i b i t o r y
sera (Salvin et a l . ,
f a c t o r (MIF) a c t i v i t i e s in t h e i r
1973). As has a l r e a d y been mentioned, alpha and gamma
i n t e r f e r o n s can mediate MIF a c t i v i t y
( T h u r m a n et a l . ,
1985; Varesio et a l . ,
1984a). Alpha and beta i n t e r f e r o n s , had
activating
capabilities
(Dean
1982). They were less e f f i c i e n t ,
and
in a d d i t i o n to gamma, have also
Virelizier,
1983;
Herberman
et
al.,
h o w e v e r , when compared w i t h gamma on the
Sone, 1986). Cytokines i.e.,
have
the
infectious
capacity
agents
conditioned
and
medium
(Hoover et a l . ,
other
than
tumor
(Wing
cells.
et
1983)
and
1982),
1984; Lee et a l . ,
supernates
of
T
have
may also be MAFs, the k i l l i n g of v a r i o u s
been
lymphocyte
found culture
in
L
cell
supernates
1985), s u p e r n a t e s of l y m p h o c y t e cell lines 1986; and Meltzer et a l . ,
cloned T l y m p h o c y t e s ( A n d r e w et a l . , al.,
interferons
These
al.,
1986; Nacy et a l . ,
(Kleinerman et a l . ,
the
to a c t i v a t e macrophages f o r
1984; Gemsa et a l . ,
lymphocyte
1982), those of
1983; Krammer et
hybridomas
( K r a m m e r et
al.,
1983). Some of these r e p o r t s a r e h i g h l y c o n v i n c i n g ; h o w e v e r , o t h e r s must be viewed w i t h
reservations,
concentrations
below
for the f o l l o w i n g reasons. F i r s t ,
one
unit
can
have
marked
gamma i n t e r f e r o n
activating
effects
on
macrophages u n d e r a p p r o p r i a t e c o n d i t i o n s . Given t h a t the a n t i v i r a l assay f o r i n t e r f e r o n is not p a r t i c u l a r l y s e n s i t i v e , i n a b i l i t y to d e t e c t a n t i v i r a l a c t i v i t y in a p r e p a r a t i o n t h a t has macrophage a c t i v a t i n g a c t i v i t y that
interferon
is
not
present.
Second,
a c t i v a t i n g agents from i n t e r f e r o n activators
could
claims
of
is not clear evidence physical
separation
of
can be questioned on the basis t h a t small
be cleavage f r a g m e n t s
of
interferon.
To date,
we do not
know w h e t h e r o r not i n t e r f e r o n molecules contain separate f u n c t i o n a l domains. If they do, it is conceivable t h a t a f r a g m e n t could have a c t i v a t i n g c a p a b i l i t i e s without
antiviral
antibody
to
interferon.
bind
activity.
Third,
an a c t i v a t o r
failure
of
a
is not p r o o f that
monoclonal
anti-interferon
the a c t i v a t o r d i f f e r s
S u f f i c i e n t a n t i g e n i c d i f f e r e n c e s e x i s t between d i f f e r e n t
from
regions of
the i n t e r f e r o n molecule t h a t a monoclonal a n t i b o d y could b i n d one f r a g m e n t of i n t e r f e r o n b u t not a n o t h e r (Russell, J . , et a l . ,
1986). F o u r t h , the f i n d i n g of
d i f f e r e n c e s in the s p e c t r u m of functional a c t i v i t i e s induced by M A F - c o n t a i n i n g supernates from d i f f e r e n t
T cell clones is not s u f f i c i e n t
to conclude t h a t a
d i f f e r e n c e e x i s t s between two p u t a t i v e a c t i v a t o r s . The a c t i v i t y of each such supernate
is
the
net
of all
of
the
i n d i v i d u a l T cell clone, not just MAF.
lymphokines
that
are
p r o d u c e d by an
O t h e r c y t o k i n e s could be p r e s e n t t h a t
modify the effect of MAF in biological assays, such as t u m o r cell k i l l i n g . While
149
t h e s e c a v e a t s must MAFs
other
issue.
than
be c o n s i d e r e d interferon,
one c l e a r l y
must
whether or not there are
keep
an
open
mind on t h e
No one has y e t p r o d u c e d a c o m p e l l i n g a r g u m e n t as to w h y t h e r e should
be o n l y one M A F . cloned,
However,
L l o y d OId's p a r a p h r a s e o f D e s c a r t e s ,
therefore
it e x i s t s '~ ( O l d ,
reminder
that
technology
activators
are
the the
thereof).
Those
interferon
will
to
rigorous
have
purification
existence
of
extant
to
different
who
to
their
have
than
unequivocally
an
investigations
and c h a r a c t e r i z a t i o n MAF
prove
t h a n one o f t h e
claim
extend
another
"It's
been
1985), s h o u l d be r e g a r d e d as a h u m o r o u s
is
same as o r
derivative
the
w h e n assessing
activator to
the
or cloning and
one
of
the
whether
interferons
(or a
other
level
than
of
either
sequencing
before
interferons
can
be
fully
accepted. 5.2.2
Macrophacje-mediated microbicidal activity O x y g e n d e p e n d e n t and i n d e p e n d e n t m i c r o b i c i d a l p r o d u c t s a r e
produced
by
macrophages
(Ockenhouse
et
identified
phagocytic
1980).
in
al.,
in
response
1984). cells
The
to
most
is t h e
stimulation important
so-called
by
gamma
killing
K l e b a n o f f system
It is d e p e n d e n t on t h e i n t e r a c t i o n o f h y d r o g e n
interferon
mechanism
yet
(Klebanoff,
peroxide (H202)
with
one o f the h a l i d e ions and p e r o x i d a s e . Gamma i n t e r f e r o n e n h a n c e d the a b i l i t y t h a t m a c r o p h a g e s had to p r o d u c e H20 2 ( M u r r a y
et a l . ,
1983; N a t h a n et a l . ,
1983). With t h e e x c e p t i o n o f MIF, w h i c h may e i t h e r be t h e same as o r r e l a t e d to gamma i n t e r f e r o n
( T h u r m a n et a l . ,
of other cytokines,
including
e i t h e r to s t i m u l a t e H20 2 p r o d u c t i o n T o x o p l a s m a ( N a t h a n et a l . ,
or
were
et a l . ,
required;
1984), a v a r i e t y lacked the ability
to increase t h e i n t r a c e l l u l a r k i l l i n g o f
to i n d u c e e i t h e r a maximal m i c r o b i s t a t i c h o u r s to d a y s o f s t i m u l a t i o n
no e f f e c t was seen i f m a c r o p h a g e s w e r e i n f e c t e d b e f o r e t h e y
R o t h e r m e l et a l . ,
( M u r r a y et a l . ,
1983; N a t h a n et a l . ,
1983;
1983). Although
provide
interferons,
1983) o r m i c r o b i c i d a l e f f e c t ,
w e r e e x p o s e d to gamma i n t e r f e r o n
often
beta
1984).
F o r gamma i n t e r f e r o n (Rothermel
1985; V a r e s i o et a l . ,
alpha and
either
macrophages with
gamma
interferon
or
l y m p h o k i n e alone can
an e f f e c t i v e a n t i m i c r o b i a l s t i m u l u s ,
in o t h e r
i n s t a n c e s t h e r e is t h e r e q u i r e m e n t f o r a second signal ( B u c h m u l l e r and Mauel, 1979;
K r a m m e r et a l . ,
vitro
by
activating
mediate c y t o t o x i c i t y is
an
important
1985). When m a c r o p h a g e s a r e no l o n g e r s t i m u l a t e d in
factors,
at
least
in
some instances
their
capacity
is lost o v e r a p e r i o d o f d a y s ( N a t h a n et a l . ,
consideration,
because
loss
of
the activated
to
1983). T h i s
state
in
vivo
w o u l d mean t h a t m a c r o p h a g e s w o u l d h a v e d i m i n i s h e d h o s t d e f e n s e c a p a b i l i t i e s . One
mechanism b y
which
macrophages could
be d e p r i v e d
in v i v o o f gamma
150
interferon
in t h e i r
e n v i r o n m e n t is t h r o u g h
t h e n e g a t i v e r e g u l a t o r y e f f e c t of
PGE 2 on l y m p h o k i n e p r o d u c t i o n b y T l y m p h o c y t e s ( E d w a r d s et a l . , 5.2.3
1986).
N o n s p e c i f i c k i l l i n 9 of t u m o r cells Many of the f e a t u r e s of macrophages a c t i v a t e d f o r t h e k i l l i n g
of m i c r o o r g a n i s m s a r e s h a r e d b y m a c r o p h a g e s a c t i v a t e d to k i l l t u m o r c e l l s . fact,
most of
macrophages
the c h a r a c t e r i s t i c s (see
section
h a v e been a c t i v a t e d The
for
first
5.2.1, the
described
above)
killing
apply
equally
to m a c r o p h a g e s t h a t
of e i t h e r m i c r o o r g a n i s m s o r t u m o r c e l l s .
r e m a i n d e r of t h i s r e v i e w summarizes f i n d i n g s
t u m o r cells as the t a r g e t f o r k i l l i n g . findings
In
b y Mackaness f o r a c t i v a t e d
t h a t h a v e been made w i t h
It is l i k e l y ,
however,
a r e g e n e r a l l y a p p l i c a b l e to t h e a c t i v a t e d s t a t e ,
t h a t many of t h e
g i v e n the s i m i l a r i t i e s
t h a t e x i s t b e t w e e n a c t i v a t i o n f o r k i l l i n g m i c r o o r g a n i s m s and t u m o r c e l l s . Mixtures interferon
can
interferon
of
gamma
be more e f f i c i e n t
used
alone
(Pace
in
et
interferon inducing
al.,
and
either
alpha
tumoricidal activity
1985;
Schultz,
or
beta
than either
1982).
Quantitative
c o m p a r i s o n s of the a c t i v a t i n g effects o f i n t e r f e r o n s and m i x t u r e s o f them h a v e revealed
that
interferon were
priming
can
the
yield
response
activating
effects
in
results
between such
used
in
the
vitro
condition
mixtures
strictly
by
the
of
of
(Pace
interferons
and
laboratories
are
investigations.
likely
alpha
et
al.,
1985).
or
cell
beta
killing,
Potentiation
of
has not a l w a y s been d e t e c t e d , due
1981). Such d i f f e r e n c e s
to
differing
experimental
m a t u r a t i o n a l state of the macrophages
Whether o r
r e l e v a n c e to h o s t
either
a m o u n t of t u m o r
1984; Boraschi and T a g l i a b u e ,
as t h e source a n d / o r has
gamma
predicted
additive
mixtures
h o w e v e r (Blasi et a l . , conditions,
by
more t h a n
not p o t e n t i a t i o n o b s e r v e d
under
in
defense in v i v o is n o t y e t k n o w n and
must be d e t e r m i n e d if we a r e to u n d e r s t a n d f u l l y the r e g u l a t i o n of a c t i v a t i o n in t h e l i v i n g a n i m a l . Interferon-induced killing
results
current
time,
rather
activation of macrophages for
in a c o n s t e l l a t i o n o f s u b c e l l u l a r these must
be r e g a r d e d as c h a n g e s
t h a n c a u s a l l y r e l a t e d to,
t u m o r cell
biochemical c h a n g e s .
t h e process o f a c t i v a t i o n .
The f i r s t
of an associated biochemical c h a n g e is one o b s e r v e d b y B o n v i n i et a l . In
this
interferon
study,
treatment
of
murine
macrophages
At
the
t h a t a r e associated w i t h ,
with
recombinant
example (1986). gamma
caused an increase in i n t r a c e l l u l a r levels of S - a d e n o s y l m e t h i o n i n e ,
w i t h no a p p a r e n t i n h i b i t i o n of p h o s p h o l i p i d m e t h y l a t i o n , c o n c o m i t a n t w i t h t h e acquisition of tumoricidal activity. macrophages refractory
T h e d e p l e t i o n o f S - a d e n o s y l m e t h i o n i n e made
to a c t i v a t i o n b y gamma i n t e r f e r o n .
These f i n d i n g s a r e
in c o n t r a s t to o b s e r v a t i o n s made o f human p e r i p h e r a l blood m o n o n u c l e a r cells t r e a t e d w i t h e i t h e r a l p h a o r beta i n t e r f e r o n ( B o u g n o u x et a l . ,
1982). In these
151
earlier
studies,
i n t r a c e l l u l a r pools of S - a d e n o s y l m e t h i o n i n e were u n a f f e c t e d ,
while the m e t h y l a t i o n o f p h o s p h a t i d y l e t h a n o l a m i n e was i n h i b i t e d . The d i f f e r i n g results
could
be e x p l i c a b l e on
several
bases,
including
differences
in the
species from which the cells came, d i f f e r e n t p o p u l a t i o n s of cells and times of treatment, critical
as well as d i f f e r e n t
one.
For instance,
interferons.
The l a t t e r d i f f e r e n c e can be a
Blasi and h e r colleagues (1984) found that mouse
peritoneal
macrophages
treated
synthesis,
developed c y t o l y t i c
with
cycloheximide,
to
prevent
protein
a c t i v i t y in response to gamma i n t e r f e r o n ,
but
d i d not i f the a c t i v a t i n g a g e n t was e i t h e r alpha or beta i n t e r f e r o n . Changes receiving
close
because
of
in c e l l u l a r p r o t e i n s induced by the i n t e r f e r o n s are
scrutiny.
the
Protein
general
phosphorylation
importance
this
is of
biochemical
r e g u l a t i o n of many i n t r a c e l l u l a r processes. Weiel et al. four
proteins
masses
that
in macrophages of are
28,
phosphorylated
33,
particular
reaction
interest
has
in
the
(1986) have i d e n t i f i e d
37 and 67 kDa a p p a r e n t molecular
after
mouse
peritoneal
macrophages
are
t r e a t e d with e i t h e r b a c t e r i a l l i p o p o l y s a c c h a r i d e (LPS), p h o r b o l e s t e r o r gamma i n t e r f e r o n and LPS. A l t h o u g h they d i d not measure t u m o r i c i d a l a c t i v i t y in this study, were
the amounts o f LPS a n d , e s p e c i a l l y , gamma i n t e r f e r o n plus LPS that used
killing. that were
should
Work
protein
have been s u f f i c i e n t
from this
to induce a c t i v a t i o n and
same l a b o r a t o r y
(Hamilton et a l . ,
tumor cell
1985a) suggested
kinase C may be a c t i v a t e d in mouse peritoneal cells when they
treated
with
gamma
interferon,
a c t i v a t o r s of p r o t e i n kinase C ) , peritoneal
macrophages
relevance
of
observations
these by
for
Johnson
and
that
phorbol
esters
(known
t o g e t h e r w i t h calcium ionophore, could prime
tumor
findings
and
cell
remains Tortes
killing
(Somers
to
determined
be
et
(1985) and Wright
al., in
1986). light
et al.
The
of
(1985)
the that
calcium i o n o p h o r e alone could s u b s t i t u t e in t h e i r studies f o r gamma i n t e r f e r o n in the a c t i v a t i o n p r o c e s s . Quantitative
and
qualitative
changes
in
the
expression
of
p r o t e i n s in macrophages t r e a t e d w i t h a c t i v a t i n g agents have also been sought (Mackay
and
Russell,
separation
of
three
could
that
1986).
35S-methionine be used
By
means of
two dimensional e l e c t r o p h o r e t i c
labeled p r o t e i n s ,
to c o n s t r u c t
these i n v e s t i g a t o r s
phenotypes
that
mark
the
identified various
stages of macrophage a c t i v a t i o n . The p r o t e i n p47b (47 kDa a p p a r e n t molecular mass)
was
exposing
expressed
them
by
mouse
macrophages
to one of the i n t e r f e r o n s .
when cells were t r e a t e d w i t h
LPS,
that
This
Cellular
been
"primed"
by
was also e x p r e s s e d
b u t o n l y because such t r e a t m e n t caused
the macrophages to secrete a l p h a / b e t a i n t e r f e r o n s , p r i m e d the cells;
had
protein
which then stimulated and
p r o t e i n s t h a t were a l t e r e d in t h e i r e x p r e s s i o n by
e x p o s u r e o f macrophages to a second, t r i g g e r i n g a g e n t ,
such as e i t h e r heat
152
killed
Listeria
associated
with
monocytocjenes
or
activation,
and p73 (71 and
p71
LPS,
included
two
that
73 kDa,
were
closely
respectively).
It
remains to be shown w h e t h e r o r not t r i g g e r i n g t h a t is associated w i t h o t h e r compounds (Hamann
and and
phenotypes, pq7b
mediators, ~ i n c l u d i n g
but
Krammer,
not
contained
1985),
Mackay and
all
p71/73, three
Russell while
proteins.
lymphokines
induce
other
expression
than
of
interferon
p71/73.
As
to
showed that primed macrophages e x p r e s s e d
mouse macrophages that Expression
of
these
were
proteins
fully
activated
waned
in v i t r o
concomitant w i t h loss of c y t o l y t i c a c t i v i t y a f t e r a c t i v a t o r s had been removed. The a b i l i t y to q u a n t i f y a c t i v a t i o n stages in v i v o , i . e . ,
in lesions, could o f f e r
a new approach to e v a l u a t i n g the efficacy of immunomodulators. A biochemical change t h a t is associated w i t h and q u i t e l i k e l y involved
in
calcium.
activation
is an
increase
in
the
concentration
of
One piece of evidence Elready mentioned is t h a t calcium ionophore
can s u p p l y one o r more a c t i v a t i o n signals (Johnson and T o r r e s , et
al.,
intracellular
1985;
Wright
et a l . ,
1985).
Whether
this
is
due
1985; Somers
to an
influx
of
e x t r a c e l l u l a r calcium o r to the r e d i s t r i b u t i o n of i n t r a c e l l u l a r stores is not y e t c l e a r . Wright et al. (1985) have shown t h a t i n t e r f e r o n / L P S - m e d i a t e d a c t i v a t i o n of
mouse
peritoneal
dose-dependent extracellular McCulloch
calcium
(1986),
macrophage 45calcium
cell
during
macrophages
fashion
by
is
for
calcium
important.
studying line,
tumor
cell
channel
killing
is
blockers,
On the o t h e r h a n d ,
inhibited
in
suggesting
that
G o r e c k a - T i s e r a and
the l y m p h o k i n e - m e d i a t e d a c t i v a t i o n of the mouse
RAW
264,
could
detect
activation,
and
three
different
no
increase
channel
in
uptake
blockers
had
of no
effect on the a b i l i t y of l y m p h o k i n e / L P S to induce the e x p r e s s i o n of t u m o r i c i d a l activity.
Furthermore,
G o r e c k a - T i s e r a and her colleagues have demonstrated
i n t r a c e l l u l a r f l u x e s of calcium in association w i t h a c t i v a t i o n of RAW 264, as well as the the i n h i b i t i o n of d e v e l o p m e n t of c y t o l y t i c a c t i v i t y by a n t a g o n i s t s of i n t r a c e l l u l a r calcium ( G o r e c k a - T i s e r a et a l . , calcium
may
calmodulin
be
involved
also i n h i b i t
in
the
1986a). A final indication that
activation
process
the i n d u c t i o n of c y t o l y t i c
is
that
activity
by
also
been
inhibitors
of
interferon/LPS
( G o r e c k a - T i s e r a et al. 1986b; Wright et a l . , 1985). Decreased
RNA
synthesis
has
association w i t h macrophage a c t i v a t i o n {Varesio et a l . ,
identified
in
1983, 1984b). A l t h o u g h
the phenomenon has y e t to be i n v e s t i g a t e d w i t h defined r e a g e n t s , it is l i k e l y t h a t the e f f e c t o b s e r v e d is due to the combined action of i n t e r f e r o n and a triggering phenomenon lymphokine
agent
(LPS,
(Varesio, and
LPS
in 1985)
are
these has
studies). shown
characterized
by
that an
Additional
analysis
macrophages imbalanced
of
treated
the with
accumulation
of
mature ribosomal RNA w i t h decreased accumulation of 28S, compared to 18S
153
ribosomal RNA. nor
was
L y m p h o k i n e alone d i d not p r o d u c e a decreased 28/18S r a t i o ,
the
change
found
macrophages.
These f i n d i n g s
alteration
RNA
in
activation, that
metabolism
perhaps
are
in is
to allow
otherwise
held
primed
or
led the a u t h o r one
the
in
inflammatory
(i.e.,
elicited)
to speculate t h a t the o b s e r v e d
that
occurs
late
in
the
process o f
e x p r e s s i o n of e x t a n t c y t o t o x i c c a p a b i l i t i e s
check
until
ribosomal
RNA
metabolism
is
down-regulated. A final and most i m p o r t a n t s u b c e l l u l a r change is the one that confers
on
cells.
macrophages the
The
binding
likely
site
capacity
explanation
on
for
activated
to
distinguish
neoplastic from normal
this phenomenon is the d e v e l o p m e n t o f a
macrophages
that
allows
them
to
interact
p r e f e r e n t i a l l y w i t h neoplastic cells (Marino and Adams, 1980; Piessons, Macrophages inhibited inhibitors Such
activated
with
in t h e i r a b i l i t y that
results
interfered suggest
macrophages
may
recombinant
to kill b y with
that
gamma
interferon
the
LPS
were
70% when t a r g e t cells were t r e a t e d w i t h
oligosaccharide processing binding
recognize
and
1978).
site
that
(Mercurio,
develops
carbohydrates,
on
1986}.
activated
specifically
complex
a s p a r a g i n e - l i n k e d o l i g o s a c c h a r i d e s , on the surfaces o f t u m o r cells. The k i l l i n g
mechanism(s)
used by
a c t i v a t e d macrophages to
kill t u m o r cells may u l t i m a t e l y p r o v e to consist o f multiple e n t i t i e s . One such entity
is the monokine, t u m o r necrosis f a c t o r ( T N F ; Old,
1986).
Gamma
produce
TNF
interferon when
increased
they
were
the
capacity
stimulated by
that
1985; U r b a n et a l . , macrophages had
interleukin
to
2 (Nedwin et a l . ,
1985). 5.2.4
Maintenance of a c t i v a t i o n f o r t u m o r cell kill in~! Once macrophages a r e a c t i v a t e d ,
retain
their
capacity
vitro,
when
removed from a c t i v a t i n g
lose t h e i r a b i l i t y
to
kill
to k i l l .
if
they
are
it
is
essential
that
they
to remain maximally e f f e c t i v e .
stimuli,
In
a c t i v a t e d macrophages q u i c k l y
One cause o f such loss is the n e g a t i v e r e g u l a t o r y
effect t h a t p r o s t a g l a n d i n E 2 has been shown to have on a c t i v a t i o n ( S c h u l t z et a l . , 1978; T a f f e t and Russell, 1981). The o b s e r v a t i o n cultures
contain
a
factor
that
e x p r e s s i o n of c y t o l y t i c a c t i v i t y
that
supernates from stimulated l y m p h o c y t e
prevents
PGE 2 from
( T a f f e t et a l . ,
down-regulating
the
1981) led to the d i s c o v e r y that
the l y m p h o k i n e r e s p o n s i b l e is gamma i n t e r f e r o n (Russell and Pace, 1984b). In l i g h t of t h i s o b s e r v a t i o n , one must t h i n k o f gamma i n t e r f e r o n not only as an activator,
b u t also as a l y m p h o k i n e t h a t maintains c y t o l y t i c a c t i v i t y ,
has been i n d u c e d . activation
Alpha/beta
interferons
in the presence of PGE 2 b u t ,
once i t
also had the c a p a c i t y to maintain
like t h e i r c a p a c i t y to a c t i v a t e ,
they
154
were less e f f i c i e n t than gamma when compared on an a n t i v i r a l basis (Russell and Pace, 198qa). 6.0
CONCLUSIONS D u r i n g the past decade, t h e r e has been a s u b s t a n t i a l increase in what is
known this
a b o u t mononuclear phagocytes and t h e i r brief
summary
interferons,
of
especially
the
recent
functions.
literature
gamma i n t e r f e r o n ,
are
has
critical
It is hoped t h a t
made
clear
that
the
as stimuli t h a t affect
e v e r y t h i n g from the d i f f e r e n t i a t i o n of these cells to the i n d u c t i o n of many of their of
functions.
information
T h e r e is l i t t l e d o u b t that an e q u a l , o r even g r e a t e r amount will
be f o r t h c o m i n g d u r i n g
the n e x t decade.
From this new
body of k n o w l e d g e we will u n d o u b t e d l y develop a c l e a r e r u n d e r s t a n d i n g of how i n t e r f e r o n s i n t e r a c t w i t h o t h e r c y t o k i n e s as p a r t of a n e t w o r k of stimuli that
regulates
the
host
defensive
functions
of
macrophages.
Once
the
r e g u l a t o r y n e t w o r k has been d e f i n e d and the specific mediators have become available,
it
mononuclear may f i n d ,
may
be
possible
to
realize
the
therapeutic
potential
that
phagocytes have a g a i n s t infectious and neoplastic diseases. We
in fact,
t h a t George B e r n a r d Shaw was more c o r r e c t than has been
p r e v i o u s l y t h o u g h t when he had one of his c h a r a c t e r s in the Doctor's Dilemma (1913) exclaim: " T h e r e is at bottom only one g e n u i n e l y scientific t r e a t m e n t f o r all
diseases,
and
that
is
to
stimulate
the
phagocytes.
Stimulate
the
phagocytes." 7.0
LITERATURE CITED
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