Cytokines and their receptors in the central nervous system: Physiology, pharmacology, and pathology

Pharmacol. Thu. Vol. 69, No. 2, pp. 85-95, C opyright 0 1996 Else&r Science Inc.

1996

ISSN 0163-7258/95 $32.00 SSDI 0163-7258(95)02033-O

ELSEVIER

Editors: 1. C. Buckingham

Associate

and G. E. Gillies

Cytokines and Their Receptors in the Central Nervous System: Physiology, Pharmacology, and Pathology Nancy _I. Rothwell,‘” Giamal

Luheshi,

and Sylvie Toulmond

SCHOOL OF BIOLOGICAL SCIENCES, ROOM

UNlVERSITYOFMANCHESTER.OXFORD

1.124, STOPFORD BUILDING, ROAD,MANCHESTERM13 9PT,UK

ABSTRACT. Numerous cytokines and their receptors have been identified in the brain, where they act as mediators of host defence responses and have direct effects on neuronal and glial function. Experimental tools for studying cytokine actions, their source and control of synthesis in the brain, actions and mechanisms of action will be reviewed here. In particular, the cytokines interleukin-1, interleukin-6, and tumour necrosis factor-a have been implicated in the central control of responses to systemic disease and injury and activation of fever, neuroendocrine, immune, and behavioural responses. The recent discovery of specific inhibitors of cytokine synthesis, release, or action may offer significant therapeutic benefit. PHARMACOL. THER. 69(2): 85-95, 1996. KEY

WORDS.

Cytokines,

brain, neuroimmunology,

neurodegeneration.

CONTENTS . . . . . . . .. . . .. . . . . 1. INTRODUCTION TOOLS FOR 2. EXPERIMENTAL STUDYING CY-IDKINES IN THE CENTRAL NERVOUS SYSTEM . . .. . . . ENTER 3. CAN PERIPHERAL~YMKINES THE BRAIN? . . . . . . . . . . . . . . . . . . . . SYNTHESIS IN THE 4. CYT~KINE BRAIN ,....................... IN THE 5. ACTIONS OF CYT~KINES BRAIN .. . . . .. . . . . . . .. . . . . .. . . . 5.1. CYT~KINES ASMODULATORSOF HOSTDEFENCE RESPONSES . .. . .

85

86 86 86 87

5.2.

EFFECTSOFCYTOKINESON CELL FUNCTION WITHINTHE BRAIN . . . . . . . . . . . . . . . . . . . . 6. CYT~KINE RECEPTORS IN THE BRAIN . .. . . .. . .. . . .. .. . . . .. . . OF ACTION .. . . .. . . 7. MECHANISMS 8. ENDOGENOUS INHIBIMRS OF CYTOKINE ACTION . .. . . . . .. . . .. IN DISEASE .., . 9. BRAIN CYT~KINES ..,............,. 10. CONCLUSIONS REFERENCES . . . .. . . . .. . . .. . . .. . . . .

88 90 90 91 92 92 92

87

ABBREVIATIONS. AMPA, cY,amino-3-hydroxy-5-methyl-4-isoxazolepropiona~e; CNTF, ciliary neurotrophic factor; CRH, corticotrophin releasing hormone; CSF, cerebrospinal fluid; GABA, y-aminobutyric acid; HPA, hypothalamic-pituitary-adrenal; i.c.v., intracerebroventricular; IFN, interferon; IL, interleukin; IL-lra, IL-I receptor antagonist; LIF, leukaemia inhibitory factor; LPS, lipopolysaccharide; LTP, longterm potentiation; MHC, major histocompatibility complex; NGF, nerve growth factor; NMDA, Nmethyl-n-aspartate; PG, prostaglandin; RT-PCR, reversed transcribed-polymerase chain reaction; TNF, tumour necrosis factor.

1. INTRODUCTION Cytokines are a large and diverse group of polypeptides with important established and emerging roles in CNS function and pathology. Because

of their

cytokines about

are not feasible, and are most

and

as mediators

[IL]-6), and that others effects

Several these

at distant cytokine

actions

some

with other

and

precise they

range

definitions

produced

However, physiological act as endocrine

there

of

in size from

and act locally to modify

suggestions

in response

tissue

to tissue

are exceptions

that some cytokines

to these can act

grouped of the

members

related

Indeed,

there

(e.g., interleukin

hormones

(e.g., IL-6), which

evidence

been

identified

on the basis of logical

ILs share

little

of the family,

sequence

(Table

I), but

criteria homology

and are sometimes

since, or more

are

author.

of other

families

always

considered

that different, factor

a receptor

family,

This review

survival

(e.g., Persson

1993) and cytokines

growth

in detail elsewhere. with

describe

their

diverse

relationships

1992).

factors with

and

Rao,

volumes,

1994; Klein,

other

and Johnson, 1994) have

we will concentrate

[TNFs]),

findings.

effects on neuronal

1993; Deckwerth

in the brain

or their

but instead,

and experimental

Therefore,

actions

necrosis

to recognize

(Hall

and their

(e.g., Campenot,

such inhib-

the same receptor,

all of the cytokines

concepts

and Ibanez,

cytokines,

on their ability

now form several

on neurotrophins

and Since

and leukaemia

by sharing

based

in detail

to cover general studies

unrelated

developing

will not cover

since this could

will attempt

covered

of cytokines, is now

facrors.

as cytokines.

(CNTF),

itory factor (LIF) can exert their activity a new classification

such as growth

over use of the term “cytokine:

neurotrophic

ILs and tumour *Corresponding

not

is now emerging

as IL-6, ciliary

Extensive have

to members is disagreement

neurotrophins

receptors,

functions

sites.

“families”

are not always

for example,

released

commonly

including of normal

simple

but in general,

inflammation.

generalisations,

have

nature,

8-26 kDa, are usually

function, injury

varied

closely

(particularly,

but where molecules

been

on those certain

relevant, or families.

will

N. 1. Rothwell

86 to enhance

TABLE 1. Main Groups of Cytokines

activity),

they are usually species-specific

et al.

and must be

accessible to the site of action and bind rapidly enough to prevent

Interleukins (IL) Tumour necrosis factors (TNF) Interferons (IFN) Neurotrophins Growth Factors

activation

01, /3

of the receptor (van Oers and Tilders,

mental approach that should prove particularly tion of cytokine

synthesis

is antisense

This approach has been successfully sion in vitro (Fujiwara antisense

See Hopkins and Rbthwell (1995) for further details.

oligonucleotide

1992), and local injection

into the brain

to block expression ofpeptides antisense

inhibition

or receptors (Wahlestedt et al., 1993). expression in the CNS,

prior to a specific stimulus

useful experimental

of

already has been used

Since cytokines show quite low constitutive

2. EXPERIMENTAL TOOLS FOR STUDYING CYTOKINES IN THE CENTRAL NERVOUS SYSTEM

treatment.

used to block IL-1 gene expres-

and Grimms,

oligonucleotides

1991). An experi-

valuable for inhibi-

strategy. Another

is likely to be a

approach is the use of genet-

The study of cytokine action has been hindered by a virtual absence

ically modified rodents, in which the gene encoding for one specific

of stable, nonpeptide

cytokine

specificity

of some cytokines,

tutive expression Further

receptor agonists and antagonists,

immunoassays, occurring

and the very low levels of consti-

of most of these molecules

complications

binding

proteins,

many tissues and extracellular available for most cytokines. standards/ligands)

improving

Nonetheless,

are

receptors

are

cytokines

because

(for

of their relative

and greater specificity,

immuno-

but commercially

Bioassays not

in

for the rat, the species of choice

assays are now being used increasingly,

consuming,

bio- and

are often species-

lack of recombinant

sensitivity,

“kits” are often expensive. and

and soluble

The immunoassays

and antibodies

for many neurobiologists.

sensitivity

between

fluids. Bio- and immunoassays

specific, and there is a notable

of

and their receptors.

arise from discrepancies

which may be explained by the presence of naturally

inhibitors,

simplicity,

the species

available

usually offer the advantage

species-specific,

and can be affected by inhibitory

et ul., 1992, for a review on cytokine

but

often

time-

molecules (see Thorpe

detection

by immunoassays

is either

transfection

Identification they can induce mentioned

able. Receptors

for cytokines

at low occupancy

antagonists

and, as

generally are not avail-

have been identified in neurones

and

glia in vitro (Ban et al., 1993; Sawada et cd., 1993) and have been localised

in the brain by in slm hybridisation,

cytochemistry, of the binding confusing

RTPCR,

immuno-

and radioligand binding (Farrar et ul., 1987). Studies of radiolabelled

data,

probably

cytokines

because

in brain have yielded

of technical

difficulties

in

producing high-affinity labelled ligands that retain biological activity. Identification

of receptor mRNA (by in situ hybridisation

or of the protein

itself (immunocytochemistry)

(Ban et al., 1991; Schohitz

or RTPCR)

has also been

et ul., 1992; Luheshi

et d.,

levels are close to the limits of

of in situ hybridisarion

and Northern

assays and immunocytochemistry. mRNA

(see Taverne, 1993,

are often expressed at low density (<50/tell),

signal transduction

above, competitive

unpublished).

scribed

(viral

of cytokine receptors has proven equally problem-

atic. These receptors

achieved

both message and protein

or overexpressed

mice have been developed for several cytokines

and bioassays). Tissue cytokines can also be localised and quantified tions,

(knockout)

copies of the gene), and already such

for a review).

by measurement of encoding mRNA. However, under normal condidetection

inactivated

of numerous

blots,

Amplification

by the polymerase

chain

been widely used to detect cytokine

immuno-

of reverse tran-

reaction

expression

(RTPCR)

has

in many tissue&,

3. CAN PERIPHERAL Peripheral

immune

CYTOKINES ENTER THE BRAIN?

cells, such as macrophages

which are a rich source of certain

cytokines,

and neutrophils, can enter the brain

including brain (Laye et al., 1994). H owever, in addition to problems

during infection,

of quantification,

However, such entry is limited and usually delayed compared

high levels of amplification

can yield false-positive

results in brain tissue due to the presence of blood monocytes macrophages

or

that show relatively high levels of cytokine expression.

With very few exceptions,

most studies now use recombinant

injury or breakdown

that seen in peripheral ically significant

quantities

as “agonists!’ It should be noted that these are normally

that has focussed

expressed

in Escherichia coli, and endotoxin

molecule

at very low levels) can influence murine cytokines,

some measurements.

(even

Human and

which are the most readily available, are usually

effective in other species, although

some, for example interferons

tissues (Andersson

harrier.

hrain in biolog-

is a matter of controversy

and debate

mainly on IL-l. Like most cytokines,

IL-1 is a

large enough to he unlikely to enter the brain by passive

diffusion,

and several groups have failed to detect

IL-1 in the CNS Dinarello,

after systemic

1988; Dunn,

injection

1988; Blatteis,

(Coccani

radiolahelled et al.,

1992). Banks

(IFNs), show marked species specificity, while others such as TNF-OI

and Gutierrez

and TNF-o( into the brain in rats under normal conditions.

(Lewis et al., 1991) in inappropriate

species.

physiological

For reasons that will be addressed later, intensive expended

on the search for inhibitors

antagonists ofcytokine antagonist occurring members

action. As yet, only one competitive

has been identified

the IL-1 receptor

antagonist

protein

that

(IL-lra).

shares

little or no agonist activity activity

and characterised

of the IL-l family (IL-la

other cytokines,

of the cytokine

have been described

is the use of anti-cytokine

We ilave observed similar transport

into the brain (Luheshi

et al., 1994), but since plasma IL-6 concen-

other

to inhibit

bodies. Such antibodies are not all neutralising

trations

can often reach lo-20

in experimental significant

bg/mL, for example,

during fever

animals and in humans, this mechanism

quantities

of IL-6

may allow

of IL-6 to enter the brain.

1991). For

that neurralise

(Engelmann

or anti-cytokine

The

less than

in nonfatal conditions.

with

and Thompson,

soluble receptors

of this system, which transports

receptor

and IL-lb) and appears to have

(Dinarello

such as TNF-a,

relevance

1% of the cytokines present in blood, is uncertain since circulating concentrations of these molecules do not usually exceed 100 pg/mL

is a naturally

homology

et al. (1993) have reported active transport of IL-1

receptor

in detail, namely

This molecule

sequence

1990). Perhaps the most widely used approach action

effort is being

and nonpeptide

1988;

et ai. (1989)

may not activate

all receptors

to

et ul., 1992). Whether

circulating cytokines can enter the “nonpathological”

cytokines

contamination

of the blood-brain

et ul.,

cytokine

receptor

anti-

(indeed, some appear

4. CYTOKINE Numerous

SYNTHESIS

IN THE BRAIN

studies have detected cytokines

in the brain or cerebro-

spinal fluid (CSF) in response to experimental conditions.

stimuli or in clinical

Indeed, it seems that most forms of local brain injury

Cytokines

and Their

or infection,

Receptors

in the Central

Nervous

System

systemic tissue damage, and even psychological

can cause increased concentrations

of cytokines

and brain (Dinarello,

1991). However,

the site of production

stress

2. Cvtokines that Induce Fever and/or Thermogenesis

TABLE

(e.g., IL-I, TNF-CY,

IL-6, LIF, and many growth factors and neurotrophins) distinguish

a7

IL-l, IL-2, IL-6, IL-8, IL-11 TNF-CY IFN-CX, IFN-P, IFN-r MIP-lc~, MIP-I& MIP-2 G-CSF, GM-CSF

in the CSF

such observations

do not

of these molecules.

Also,

an

increase in mRNA levels does not always correlate with expression of the cytokine indicate

itself (Dinarello,

that induction

the brain of experimental (Benveniste Spranger

1991). Measurements

of cytokine

of mRNA

gene transcription

occurs

in

animals in viuo, or in brain cells in vitro

et al., 1990; Lechan

et al., 1990; Schobitz

et al., 1990). Cytokine

expression

microglia

major source of cytokines

such as IL-I, IL-6, TNF-(Y, transforming

Chung

and fibroblast

and Benveniste,

representing

et al.,

Kossman et al., 1992; Araujo and Cotman, in vitro (Giulian

1992). It seems that micro(LPS)

et al., 1986) and in uiuo (van Dam et

al., 1992), but astrocytes can also produce IL-1 (Fontana et al., 1982) and their involvement (Williams

could depend on the type of brain injury

et al., 1994; Fan et al., 1993). Neurones

express cytokines

of great scientific

importance

are so numerous

as to be outside

Kluger (1991) has eloquently

are also able to

such as IL-I (Breder et al., 1988), IL-2 (Araujo

(mediator

of fever),

cytokines:

(1) production

correlates

with the response

the response

which

1989; Joseph et al., 1993) or administration Induction example,

of cytokine

of IL-1 (Fabry et&,

gene transcription

after forebrain

ischaemia

(Jirik et al., 1993).

is usually rapid, for

in the rat marked increases

in

the criteria

equally

synthesis

ical response in question. Although

physiological

action,

the increasing

this may be of clinical

of tissue damage. In addition, to affect expression

profound

activator

neural activity

of certain cytokines

development

few. However,

use of these proteins

or immunodeficient

diseases, sepsis and many other

(Patterson,

has been reported and Nawa,

are increased during

1993).

of the brain expression

associated

or whole body systems usually

affect CNS

function

directly.

Probably,

the

most

of a variety of cytokines

5.1. Cytokines as Modulators ofHost Defence Responses Challenges

with any insult to homeostasis,

pathogens,

tissue injury or inflammation,

as exercise

or psychological

ischaemia,

associated

with release of excitatory

Common

excitatory

directly

In

damage are

amino

acids (Meldrum

and

amino

acids may influence

disturbances,

synthesis and action are their close

synergy, and interactions.

notably axis),

activation

coIlectively

elicit

known

activation

systems, behaviour

gastric,

For example, in periph-

peripheral

nervous

as fever. Cytokines

have been implicated

and Hopkins,

usually manifested

(see Rothwell

and IL-6 can block IL-l and TNF-(Y gene transcription

(Dinarello,

IL-l, originally

1991; Helle et al., 1988; Schindler

not studied

presumed action as the naturally occurring

1995), and most seem to be mediated

was known as “endogenous

in detail, such a complex system is also likely to be present in brain

is, therefore, the most studied cytokine,

(Norris ef ai., 19941, presenting

sively researched

daunt-

defence

ing, situation!

aspect of cytokine

ACTIONS

OF CYTOKINES

The availability

of recombinant

IN THE cytokines

in metabolic

BRAIN

increasing

has led to a plethora

Rothwell

some cases, pyrogenic

from individual

studies, with limited concentrations

where it may be difficult to distinguish nonspecific)

sometimes

effects

endogenous molecule.

from biologically While

of a cytokine,

pharmacological important

these observations

arises

actions

(or even of the

may prove to be

and fever is the most inteneffects in the brain on host

cytokines

(Kluger, 1991). Dose-response

have been reported

peripherally,

only a few minutes)

although

into in

in humans

curves indicate that these cytokines

ate usually effective in low concentrations when injected

derives from exper-

have been injected

animals (usually rats, mice, or rabbits), responses

increases

is already quite long and still

(Table 2). Most of this information

iments in which recombinant experimental

1995). Such information

its

mediator of fever. IL-l

that elicit fever and associated

rate (thermogenesis)

of data on their actions in the brain or on isolated brain cells (see and Hopkins,

to be identified,

pyrogen”-reflecting

responses.

The list of cytokines 5.

immune

in all of these responses

by effects on the CNS. One of the first cytokines

if somewhat

[HPA]

and

increased metabolism

and altered thermoregulation,

synthesis of itself, IL-6, and other growth factors or neurotrophins,

an intrigling,

of a

(e.g., increased slow wave sleep, loss of appetite

eral tissues, TNF-a! can induce IL-I and IL-6, while IL-1 can cause

et al., 1990). Although

of

status (most

of the hypothalamic-pituitary-adrenal

cardiovascular,

(thermogenesis)

invasion

as the “host defence

and general malaise or “sickness behaviour”),

or indirectly.

features ofcytokine

interdependence,

or infection.

neuronal

of processes,

including

and even stresses, such

response!’ These include changes in neuroendocrine

neurotoxins,

most forms of acute or chronic 1990). Thus,

conditions.

with “host defence responses,” and those that seem to

ical injury, inflammation, the brain,

expression

as “biolog-

have been divided into

number

Garthwaite,

than

in view of

or their inhibitors

is damage to the CNS, irrespective of the type of insult, i.e., mechan-

cytokine

rather

relevance

mediators, viruses, and products

of some growth factors (Patterson

1993), and concentrations neuronal

prostaglan-

and (3)

ical response modifiers” to treat diseases such as cancer, autoimmune

those that modify systemic function,

such as bacterial endotoxin,

and actions,

reflect a pharmacological

but presumably

synthesis in the periphery,

of

these criteria apply to any action

of inducrion

dins (PCs), and other inflammatory

of

that

at a site and in

they have been fulfilled for relatively

largely unknown,

in brain are

and location

is administered

The mechanisms

include stimuli known to affect

pyrogen effects

(in this case fever), (2) induction

For no reason other than clarity, actions

expression

that shouId

to other

pattern

IL-l@ mRNA have been observed after 15 min (Minami et al., 1992). of cytokine

they

of action or synthesis of the cytokine inhibits the biolog-

even if effects of cytokines

and have been shown

applies

a dose that relates to its observed inhibition

cells are also a potential

or viral infection

described

when the cytokine

of cytokines,

to express IL-6 after LPS challenge

and extended,

the scope of this article.

in a temporal

et al., 1989), and IL-6 (Schobitz et al., 1992). Finally, brain endothelial source of cytokines,

when confirmed

be met to establish a role for any cytokine as an endogenous

1989; Morganti-

glial cells are the main source of IL-1 after lipopolysaccharide challenge

a

growth factors (Giulian et ai., 1986;

1990; Sawada

stimufactor.

in

glial cells, with activated growth factor-p,

protein; G-CSF, granulocyte colony granulocyte/macrophage colony stimulating

lating factor; GM-CSF,

et al., 1992;

has been reported

and astrocytes

MIP, macrophage inflammatory

(i.e., less than 1 pg/kg)

and given the short half-life (usually

of these molecules

in circulation,

they must

N. J. Kothwell et hi.

n

39.0

F

T

* rl //:

I

SERUM

:

+A

IL-IB

37.5

(I.C.V.l

37.0

IL-la (i.c.v.1

Saline-

ENDOTOXIN __t

FIGURE 1. Effects of i.c.v. injection of neutralising antibodies to IL-la or IL-10 on febrile responses to systemic endotoxin (LB, 100 &kg i.p.) in the rat. Intracerebroventricular injection of IL-l/3, but not IL-la, antiserum attenuates pyrogenic responses to endotoxin. Mean values * SEM (n = 8). *P < 0.05 vs. endotoxin alone. (ANOVA.)

act at very low concentrations.

In most cases, fever is elicited

much lower doses when the recombinant the cerebral ventricles a central

site of action

of CSF

than blood

cerebral

injection,

or directly into

1990a, 1991). These data indicate

on fever. However, some caution

exercised in this interpretation,

or high local concentrations and the lack of information

resulting

greater than

lished). Indeed, there is evidence that some cytokines, can induce fever by separate mechanisms rhe CNS, since febrile responses but not systemic, injection

such as IL-l,

to intracerebroventricular

for cytokines

llmited

of the lack of specific

actIons. Systemic injection

as endogenous

of stimuli in the rat (Smith

and Krueger,

1991a), possibly by blocking

and Kluger, peripheral

mediates

antlbody

fever derives

from studies

to IL-Ip has been injected

in which

to IL-1 or endotoxin

is

of their 1992; Opp that brain

neutralising

into the brain (see Fig. 1 and

of recombinant

(~55) in the mouse (Lewis murinc TNF-u

et ul.,

inhibits

1994). effect.

pyrogenic

In contrast, Similarly, responses

anti-IL-la

antiserum

antiserum

is without

to rat IL-6 injected

to peripheral

endotoxin

or central

administration

of IL-l/3 in the rat (Rothwell

taken together

with the data of Klir et al. (1994), indicates

IL-l/3 acts on the hrain by releasing

ul., 1994), an antipyretic 1992). Studies

(Dinarello

action

Although

that

this cytokine

et ul., 1986; Hashimoto

has been proposed

on effects of anti-TNF-cu

yielded conflicting

et ul., 1991), which

have similar

species specificity.

For

et cd., 1991), and this may also he true antipyretic

effects of human,

but not

in the rat (Fig. 2), and find the murine protein to unpublished).

to indicate

responses

to systemic

tion of IL-lra or an antibody HPA responses endotoxin

in rodents

or changes

Although

(Rivier,

data

IL-l in the brain

inflammation.

Thus,

to the IL-1 Type I receptor 1993), somnogenic

in behaviour,

avoidance behaviour (Bluthe

less extensive,

that endogenous

suppression

injec-

inhibits effects of

of appetite

or

etal., 1992). Injection ofTNF-ol mimics

these effects of IL-l, but actions of TNF-ol on the HPA axis seem to depend (Sharp

on pituitary

rather

than

et al., 1989). In contrast

hypothalamic

site of action

with other pyrogenic

cytokines,

IL-6 fails to elicit sleep in rodents (Opp et ul., 1989a), and somnogenir effects of cytokines

regulation

cytokines

even in the absence

of infection

it is now apparent that central injection

The doses required

or

1991a).

mimics many of the responses

to systemic

of cytokines

challenge

in rodents.

to elicit these diverse effects are remarkably

similar, but in many cases, no information of inhibiting

from fever (Opp

group have suggested

such as IL-I may play a role in the normal

of sleep patterns,

mjury (Opp and Krueger, Therefore,

have been dissociated

1991b). Data from Krueger’s

the synthesis

is axrailahle on the effects

or action of the endogenous

cytokine.

IL-6.

Results for TNF-cx are more complex. can induce fever in rodents

i.c.v.

While most cytokines

he a much more effective pyrogen in rodents (A. Stefferl, G. Luheshi,

that certain

significant

pyrogenic

data, however, may reflect the use

human TNF-ol.

for rats. We have observed

strated that injection of anti-IL-16

(Klir

of fever (Long et al.,

to attenuate

example, human TNF-cx hinds to only one of the TNF-ol receptors

and Krueger,

antiserum, either i.c.v. (Bushridge

reported

actions in different species, TNF-(r exhibits

Rothwell et (II., 1989; Long et al., 1990a). Two studies have demonet u1., 1989) or into the hypothalamus, in the rat inhihits fever and thermogenesis, and reduces local IL-6 release after endotoxin

IL-I

in the rat (Long et ul., 1992; Klir

et ul., 1994). These discordant

mediates other

IL-l&induced

IL-6 release (Bate et al., 1994). More powerful evidence

responses

has also been

are also available

of IL-lra potently inhibits fever induced

by a number

TNF-a

(i.c.v.),

pyrogens

inhibitors

1994; Stcfferl et al., 1994) and enhancement 1990b).

and N. J. Rothwell,

6) (Luheshi

___

FIGURE 2. The effects of subpyrogenic doses of hTNF-a (1.5 &kg, i.p.) or mTNF-a (0.3 pglkg, i.p.) on fever induced by IL-l/3 (1 pglkg, i.p.). IL-lp fever was significantly attenuated in the presence of hTNF-a, but unaffected by mTNF-cr. Subpyrogenic doses of either human or murine. TNF-(r had no effect on body temperature in salinestreated rats. Data are presented as mean f SEM (n = 8). *P < 0.01. (ANOVA.)

and in

of IL-1 are blocked by central injection

ct ul., 1993). Evidence

IL-I

unpub-

in the periphery

to the Type II IL-1 receptor (see Section

partly because

from

on the half-life of

(G. Luheshi, S. J. Hopkins, and N. J. Rothwell,

of an antibody

must be

in view of the much smaller volume

cytokines in the brain, which seems to be considerably in circulation

at

cytokine is injected within

(a few nanograms/kilogram)

specific brain regions (see Rothwell,

38.0

E”

./

+A

+

hTNF-a

t

j:p

ALONE

NON-IMMUNE

mTNF-a

38.5

W

5 ;;;

Saline

et

(Long et ul.,

Effects of Cytokines Within the Brain

on Cell Function actions

5.2.

antiserum

on fever have

In addition

results Indicating both inhibition

(Cooper et ul.,

of host defence responses to systemic infection.

to their apparent

in the brain as mediators a number of cyto-

Cytokines

and Their

Receprors

in the Central

Nervous

kines also influence neuronal and glial development, growth,

plasticity,

important

and degeneration,

in local responses

System

differentiation,

and seem to be particularly

to damage and infection.

Recent

(Giulian

and Baker,

data have implicated

and commitment made between

cytokines

of lineage,

et al., 1992).

in neuronal

development

and direct comparisons

development

systems (Patterson

1986; Brenneman

in the neuronal

E m L

IL-1 could be a modulator of neuronal and glial cell growth during development

89

have been

‘;

goao-

I_

-’

z

70 -

60 -

and haematopoietic

1 I1

and Nawa, 1993; Bazan, 1991). Even in the adult

nervous system, cytokines may affect synaptic plasticity. Long-term potentiation

(LTP) measured

in brain slices is potently

by IL-1 and other cytokines, and Nawa 1993; Rothwell

but enhanced and Hopkins,

1995, for reviews). IL-2

has also been shown to be a potent inhibitor and LTP induction

in hippocampus

effects are observed the

mechanisms

cytokines.

IL-1 inhibits

(Plata-Salaman butyric

of acetylcholine

(Tancredi

at low concentrations

are unclear

and

and Ffrench-Mullen,

acid (GABA)-ergic

release

et al., 1990). These

of the cytokines,

probably

calcium currents

inhibited

by EGF (see Patterson

in hippocampal

neurones

1994) and enhances y-amino-

currents

in cortical

cells (Miller et al.,

1991). Both of these effects are again seen at low concentrations and might inhibit synaptic plasticity. However, other reported effects of cytokines,

such as release of nitric oxide and arachidonic

and increased

intracellular

higher concentrations, and Relton,

calcium

concentrations,

complex

and dose-dependent

and survival.

For example,

in primary

of IL-l,

factors,

such

(NGF),

CNTF,

as fibroblast brain-derived

trophic

effects

and/or

neuronal

factor,

neurotrophic

neuroprotective

toxins. In some cases, neuroprotection

NGF

However, high concentrations (Araujo,

cultures,

nerve

that

synthase

inhibitors,

excito-

release potentially neurotoxic

perhaps

neurone

and

survival

of a phaeochromocytoma

induced

(Campbell

in vitro to in vioo

by intrastriatal

injection

IL-6 exhibit

of N-

acute neurodegenerative

et al., 1993). The relevance

actions

of neuronal

connections

and cholinergic

(NMDA) (Toulmond et al., 1992). However, trans-

genie mice overexpressing

immaturity

cell line (PC12)

catecholaminergic

in vitro (Hama et al., 1991) and limits the loss

neurones

methyl-o-aspartate pathology

nitric oxide cells:

et al., 1988), improves

of cytokines cultures,

and, particularly,

of complex

by the synaptic

the low level of glia. In fact, many

acid, and unidentified

1994). Although

little

a cytotoxic

activity

are an important

the brain, and are also direct targets for cytokines. glia following injury and subsequent

activated

source of cytokines Activation

glial scar formation

in of

has been

ascribed to the actions of cytokines such as IL-I and TNF-(Y (Giulian and Lachman,

1985; Selmaj et al., 1990; Bourdiol

and TNF-cy can stimulate

the synthesis

et al., 1991). IL-l

of neurotrophic

the production

towards these cells (Selmaj

IL-2 appears to act as a mitotic

Merrill,

1986) for oligodendrocytes.

Intracerebroventricular

and Raine,

1988),

agent (Benveniste

or intracerebral

injection

factors

of

exerts and

of IL-l in the

rat causes marked acrivation

ofglia, and does not inhibit ischaemic

or traumatic

rather,

(Giulian

damage

but,

1994; Loddick markedly

and Rothwell,

inhibits

damage

neurodegeneration

1994). Injection induced

(middle cerebral artery occlusion), fluid percussion or

enhances

et al., 1988; Bourdiol et al., 1991; Lawrence and Rothwell, of IL-lra,

by focal cerebral

traumatic

trauma), or pharmacological

however, ischaemia

brain damage (lateral activation

of NMDA

cY-amino-3-hydroxy-5-methyl-4-isoxazolepropionate

(AMPA)

Rothwell and Relton, 1993; Toulmond and Rothwell, and Rothwell,

1994). These protective

ible and of considerable In view of the

magnitude

apparent

reduction

of IL-lra

these forms of acute neurodegeneration

and trauma (Ginsberg protection

in the rat. This exacer-

changes

in body temperature

different

mechanisms

and Rothwell,

1994).

et al., 1993).

seems to be independent

and, therefore,

to the pyrogenic

as

worsens the effects of

et al., 1992; Clifton

by IL-lra

and

IL-1 mediates

by IL-I may be due to its activity

a pyrogen, since elevated body temperature ischaemia

in damage).

(Dinarello

1991), these data indicate that endogenous

Nevertheless,

1992;

1995; Lawrence

effects are highly reproduc-

(40-70%

selectivity

bation of neurodegeneration

and astrocytes,

concerning

it has been shown that TNF-a

whereas

1993). As previously microglia

low molecular weight molecules

is known

cytokines by oiigodendrocytes,

Thompson,

glial cells, particularly

to

factors, such as gIutamate, nitric oxide,

and Vaca, 1993; Hartung et ul., 1989; Piani and Fontana,

potentially neurotoxic effects of cytokines have been ascribed to actions on glia (Lipton, 1992; Giulian, 1993; Giulian and Vaca, discussed,

et al., 1990; Carman-Krzan these cells and micro&a

receptors in the rat brain (see Fig. 3 and Relton and Rothwell,

of these studies

may be limited

absence

arachidonic (Giulian

and are not (Strijbos

of cholinergic

blockers

above

1995). IL-6 also exerts a direct action on neuronal

it induces differentiation (Satoh

1995).

1995). The toxic

receptors,

or calcium-channel

(Gadient

against

prevented by excitatory amino acid receptor antagonists, Rothwell,

such as NGF by astrocytes

et al., 1991), but they also stimulate

and Rothwell,

known

AMPA

FIGURE 3. Neuroprotective effects of IL-lra. Percentage inhibition of neuronal damage induced by brain trauma (lateral fluid percussion injury, 72 hr), focal ischaemia (middle cerebral artery occlusion, 24 hr), striatal infusion of excitatory amino acid agonists of NMDA receptors (cis-2,4_methanoglutamate, 24 hr) or AMPA receptors (S-AMPA, 48 hr). Damage was determined histologically at the optimal time after each insult. Inhibition is compared to vehicle, and in each case, was statistically different from their respective vehicle-treated groups (depicted as 100%). P < 0.01 unpaired t-test.

factor

effects of IL-1 can be in-

and Rothwell,

are likely to activate

NMDA

neuro-

to excitotoxic

effects of IL-1 are usually seen at concentrations those

STRIATAL

STRIATAL

ISCHAEMIA

exert

of IL-1 or TNF-(Y are toxic to cultured

1992; Strijbos

TRAUMA

growth

factor,

in response

(Strijbos

2

FOCAL

TNF-cr

has been ascribed to inhibi-

calcium

action

are

growth

BRAIN

with many growth

actions

1990), and protective

by blocking

on neuronal

in common

growth

tion of the rise in intracellular agents (Mattson,

effects of cytokines

and most notably

and low concentrations

neurones

at

might be expected to enhance LTP (Rothwell

seen on other parameters,

hibited

acid

observed

1993).

Similarly

-

but

vary for different

actions

probably

of

involves

of IL-1 (Loddick

N. J. Rothwell

90 6.

CYTOKINE

Receptors

RECEPTORS

for cytokines

IN THE

BRAIN

have been identified in neurones

and glia,

and have been localised in the brain by in situ hybridisation, nocytochemistry,

and radioligand

binding.

Technical

arising from the very low density of cytokine cells, the absence of receptor antagonists, high-affinity

labelled

receptor

sites of action

but some important amus in rodents

have

correlates

well with known

exist, particularly

for IL-l, since

IL-I has been observed in the hypothal-

(see Hopkins

and Rothwell,

1995, for a review).

Receptors for IL-l, IL-2, IL-6, TNF-(r and a number of growth factors have been localised in the brain of rodents, densities in the hippocampus Rothwell,

1995; Otero and Merrill,

(see Hopkins

i.e., receptors

IL-la

IL-10

VEHICLE

and

1994), although for IL-l, mRNA but no significant binding

has been detected. An emerging feature of cytokines families,

i

and most show highest

and hypothalamus

has been identified in the hypothalamus, of receptor

*** AZL-

in the brain (e.g., for neurotrophins),

discrepancies

no binding ofradiolabelled

activity

of cytokine receptors. In several

distribution

of cytokines

on many

and problems in producing

ligands that retain biological

posed problems fur the identification cases, apparent

receptors

CRH Antagonist (25pg i.c.v.1

D

T

immu-

difficulties

et al.

is the concept

with closely related structures

FIGURE 4. Effect of i.c.v. injection of CRH antagonist (0~ helical CRHam4i, 25 pg on febrile responses to i.c.v. injection of IL-l@ (5 ng) or IL-lo (20 ng) in the rat. Mean values t SEM (n = 8-10). ***P < 0.001 vs. IL-lp alone.

or identical subunits. For example, there now exist families of singleprotein or complex receptors that recognise more than one cytokine. These

include

the IL-I Type I and II, TNF/NGF

6/CNTF/LIF

receptor

brain-derived

neurotrophic

families,

The existence

of these receptor

and the IL-

and other neurotrophins

factor (Rothwell

such as

and Hopkins,

families has challenged

the earlier

concept of single receptor, single ligand and the relationship a receptor/iigand

interaction

and confusion

in the brain. Two IL-1 receptors

peripheral

between

and a specific function.

Some of the greatest controversy receptors

1995).

exists for IL-I

have been identified

cells; an 80-kDa Type I receptor, which binds IL-lo

on and

IL-lp with similar affinity, and a 68.kDa

Type II receptor,

which

shows greater affinity for IL-l/3 (Benjamin

et al., 1990; Matsushima

et al., 1986). It has been suggested that the Type II receptor coupled to signal transduction

mechanisms

is not

and may act as a “decoy”

that neutralises IL-1 action (Sims et al., 1993). Both receptor subtypes have been identified

in rodent brain by in sittc hybridisation

PCR analysis (Parnet et al., 1994), but radioligand iodinated

IL-la)

I receptor

and has failed to show binding

binding

has revealed only sites characteristic

site of action

of IL-1 in the brain, methodological

in the hypothalamus is a major

and results of binding

problems.

(using

of the Type

(Haour et al., 1990; Ban et al., 1991). The hypothalamus may reflect

and

This

certainly

receptors

in the hypothalamus,

at this site, but subsequent

an antibody

to the IL-2 receptor

hypothalamus Functional

(Lapchak

indicating

revealed

studies have also raised questions

(Dripps

in the brain, activation;

such as behaviour,

that IL-lra inhibits Rothwell, ceptors

appetite

to earlier evidence, Further

about IL-1 receptors to the rodent Type I

mediate fever is that IL-lo (see Section

1991). For example,

effects of IL-lb,

are blocked

releasing

Fig. 4 and Section

hormone

suppression,

of IL-1

and HPA

G. Luheshi,

evidence

distinct mechanisms

trophin

sites in the

recent studies have shown

fever also (A. Stefferl,

unpublished).

thermogenesis

using

et al., 1991), clearly blocks many actions

contrary

of

1993).

in the brain. IL-lra, which binds preferentially receptor

an absence

binding

and N. J.

that different

IL-1 re-

and -0 seem to elicit fever by

7; Busbridge et al., 1989; Rothwell, but not IL-la,

by i.c.v. injection (CRH)

antagonist

on fever and

of either

a cortico-

or lipocortin-1

(see

7). An antibody (ALVA-42) raised to the purified

IL-1 Type I1 receptor

also prevents

complex (MHC) Class II antigen o( and p chains (Gayle

et al., 1994), throwing

some doubt on its specificity. However, recent

immunohistochemical 42 or an antibody

studies on the rat hypothalamus using ALVAto MHC

the ALVA-42 only, indicating the MHC

Class II showed positive S. Toulmond,

Species specificity may also be important human

TNF-ol

and N. J. Rothwell,

its injection in Section

may be mediated (e.g., TNF-o(,

for studies on TNF-ol.

binds only to the ~55 receptor,

induces

fever in rodents,

effective than rat or mouse TNF-(r described

of

data).

In rodents, although

staining

that it is binding to a site other than

Class II (G. Luheshi,

unpublished

et al., 1993).

and

it is much

less

(Stefferl et al., 1994), and data

5.1 suggest that pyrogenic

by the ~75 receptor.

actions of TNF-a

Several cytokine

receptors

IL-I Type II, IL-6) can be “shed” in a soluble form

into circulation

(Giri et al., 1990; Novick et al., 1990; Engelmann

et al., 1990; Degroote et al., 1993), but it is not known if such release can occur in the brain or CSF.

studies

immunocytochemistry

and Araujo,

compatibility

(Luheshi

has been shown to bind to major histo-

appears to

be the case for the IL-2 receptor where no binding of radiolabelled IL-2 was observed

tion of IL-lfl, but not that elicited by IL-la This antibody subsequently

fever induced by central injec-

7. MECHANISMS Multiple,

OF ACTION

complex and, in some cases, common

mechanisms

have

been proposed for the actions of cytokine on peripheral cells, some of which may be relevant

to their effects in the CNS.

Changes

in a number of second messenger systems (e.g., calcium, cyclic AMP, protein kinase C) have been reported in neurones or glia in response to cytokines (Rossi, 1993), but in most cases, have not been related to specific actions. Similarly, diverse changes in neurotransmitter systems (e.g., serotonergic,

noradrenergic,

cholinergic,

and peptides in the brain can be elicited by cytokines, of these

responses

physiological

may represent

actions

(Rothwell

pharmacological

and Hopkins,

Most of the pro-inflammatory

cytokines

TNF-ol) are potent releasers of arachidonic of PGs. Central

effects of these cytokines

responses,

behavioural

prevented

or attenuated

1991, 1992). The

changes,

primary

GABAergic) though many rather

(e.g., IL-l, IL-2, IL-6,

acid and cause synthesis on fever, neuroendocrine

and appetite suppression

by cycle-oxygenase

inhibitors

PG responsible

for cytokine

assumed to be PGEj (Coceani

than

1995).

et al., 1986; Morimoto

can be

(Rothwell, action

is

et (II., 1988),

Cytokines

and Their

Receptors

in the Central

Nervous

CRH

System

91 Inhibition

Antagonist i.c.v.1

1771l25pg

ofcalcium

currents and enhanced

GABAergic

with the observed

concentrations

of IL-l and TNF-(Y in vitro (see Section 5.2). However,

release

of arachidonic

molecules toxicity

neuroprotective

activity

are consistent

acid and nitric

may underlie,

induced

at least in part, their

in viva (Rothwell

observed

oxide

effects of low by these

apparent

and Relton,

neuro-

1993). Neuropro,

tective effects of IL-lra appear unrelated to changes in body tempera-

y

l.O-

ture, since IL-lra does not affect temperature

0

ischaemia,

and cycle-oxygenase

not affect damage significantly

2 E

0.5

-

++

***

%

Rothwell,

induced

ischaemia

zE

IL-18

Rothwell i.c.v. injection of CRH antagonist ((Y febrile responses to i.c.v. injection of ng), or TNF-a! (50 ng). Mean values f 0.01, ***P < 0.001 vs. cytokine alone.

FIGURE 5. Effect of helical CRH9_41) on IL-l/3 (5 ng), IL-6 (20 SEM (n = 7-9). **P< (ANOVA.)

and Relton,

the potential directly

actions,

for example,

by cytokines

and can mimic

on fever (Rothwell,

1990b).

presumably actions

by cycle-oxygenase

are not mediated

inhibitors,

or antinociception,

1990b).

Other

of slow wave sleep

also occur independently

of PCs and can be

or actions

Glucocorticoids, agents, inhibit

the

hypothalamus,

hormone,

and

causes

and subsequent

release. There

release

activation

is now considerable

nucleus

of adrenal

evidence

peripheral

1993). However, CRH

that are independent

nociception

certain

(DeSouza, peripheral

can all be prevented

a receptor antagonist 1990; Rothwell, also mediated

or antibody

responses actions

in induction CRH

CRH

action

using

responses

to IL-6 and IL-8 are

of IL-la

or TNF-a!

are not

1990a,c). These data provide further support

from injection to PGFz,

et al., 1993; Rothwell,

cytokine

by blocking

and anti-

(e.g., Fig. 4; Dunn and Berridge,

while actions

not blocked by a CRH antagonist (Coelho

responses,

of several distinct

The fever resulting febrile

1987). Effects of IL-I/3 on fever,

and possibly atypical IL-I receptors

for the existence

et al., 1994; in the brain

immune

1989). Pyrogenic by CRH,

(Fig. 5 and Rothwell, for multiple

actions

of the HPA axis and in some cases, are exerted

outside the hypothalamus thermogenesis,

has numerous

in the brain,

in the brain, and

of PGEz into the rat brain is or by dexamethasone

are inhibited

by both

and, yet,

by glucocorticoids

of eicosanoid

glucocorticoids

anti-inflammatory in the brain and in

and action (Dallman

(Bateman

inhibits

potential

site of inhibition,

of CRH synthesis

to IL-8 and PGF?,

in the inhib-

itors (Coelho nisolone

the febrile responses

et al., 1993). Neuroprotective

effects of methylpred-

have been shown in animal models, as well as in humans,

but at very high doses and with side effects that limit its use (Hall and Braughler, observed

1982; Hall et al., 1987), and several studies have

neurotoxic

21-aminosteroids properties, ischaemia

effects

of steroids.

lazaroids (tirilazad),

The

nonglucocorticoid

which possess antioxidative

have been shown to be neuroprotective

in the mouse

head injury, but also to limit hypoperfusion

Anti-inflammatory

actions ofglucocorticoids

also inhibits

as lipocortin-1

et al., 1992; Buckingham

et al.,

have been ascribed phospholipid

or annexin-l

the central

as IL-l@ on fever, thermogenesis,

1988).

effects of cytokines,

such

and HPA activation 1994). Lipocortin-1

is

in normal and injured rat and human brain (Strijbos

a site of considerable

interest

of its role in activation

of

and may act as an endogenous

is induced by cytokines such as IL-l and TNF-a! in peripheral tissues,

1991). Central

may also mediate some (e.g., sleep), but not all (e.g., fever) effects.

inhibits

These

striatal

in the

CNS

responses, by different

are responsible

certain

for cytokine

each appears to be activated brain regions

common

mechanisms

control

independently,

and/or different

receptors.

of systemic probably

injection

infusion

1992).

both

of recombinant receptor

of an anti-lipocortin-I

forms of damage (Relton

et al., 1991), action

(Relton

lipocortin-1 agonist

(Strijbos

is expressed

of cytokine

caused by focal cerebral

of an NMDA

while i.c.v. administration hances

inhibitor

et al., 1990) and neurodegeneration

neurodegeneration

bind-

(Flower,

but the locus coeruleus

fever (Carey

after

1988; Hall et al., 1988).

in the cat (Hall and Yonkers,

Lipocortin-1

that although

since release

of dexamethasone

are not known,

data indicate

1989).

rat brain, since neither of these is affected by cycle-oxygenase

since it apparently

nervous system. Nitric oxide, the release of which

largely

et al.,

above effects of CRH the sympathetic

Inhibition

of CRH in certain responses to cytokines

et al., 1987). Modification

known

because

glucocor-

responses.

and/or release may explain why administration potently

that decrease

has been ascribed

synthesis

another

ing protein,

sleep (Opp et al., 198913). The sites of action of the

is limited by the

exert negative feedback on CRH synthesis

1990b). CRH does not mediate all is not involved

ACTION

and exogenous

in part to the release of a calcium-dependent,

treatments

of slow wave sleep induced by IL-I, and endogenous

inhibits

and action

affect cytokine-mediated

actions

to suppression

after concussive

pathways of fever induction.

are

in positive feedback.

apparently

cells, and both endogenous

in the brain indicates

glucocorticoid

to show that CRH

resulting

scenario

synthesis

However, the involvement

of adrenocorticotropic

mediates effects of IL-1 on the HPA axis (Buckingham Rivier,

of

OF CYTOKINE

some of the most potent

of cytokine by the paraventricular

whether

of cytokines.

cytokine

1995). produced

et al., 1994;

in neurodegeneration

existence of several endogenous inhibitory mechanisms

ticoids significantly

is classically

INHIBITORS

detrimental

clearly dissociated from effects on fever (see Rothwell and Hopkins, CRH

of

are highly effective molecules that can induce their own

the synthesis

and, therefore,

by PGs (Rothwell,

of IL-I in the brain, such as induction

(e.g.,

and CRH

release and that of other cytokines, This potentially

In contrast,

pyrogenic responses to the smaller molecular weight cytokines IL-8) are unaffected

their

(Lyons et al., 1991; Strijbos

1993). It remains to be determined

8. ENDOGENOUS

is also released

injection

markedly atten-

related.

Cytokines but PGFL,

in the gerbil and focal

factor receptor antagonist

roles of IL-l

and

in neurode-

in the rat, since central

uates these forms ofdamage

TNF-a

IL-6

(Loddick

has been implicated

by global ischaemia

and excitotoxicity

a corticotropin-releasing

0

which block fever, do

after focal ischaemia

1994). However, CRH

generation

2

in animals after cerebral

inhibitors,

on

et al.,

markedly

ischaemia

or

in the rat brain, antibody

et al., 1991; Black

en-

et al.,

N. J. Rothwell

92 Effects

of lipocortin-1

ascribed

to inhibition

on peripheral

of arachidonic

inflammation

have been

acid release and hence, PC

synthesis (Flower, 1988). However, in the brain, lipocortin by modifying

the release or actions

the pyrogenic

effects of cytokines

of CRH,

since it attenuates

that act via CRH

IL-6, IL-8), but not those that act independently la, TNF-(r), Rothwell,

irrespective

of the involvement

1994). Thus, neuroprotective

(i.e., IL-ID,

of CRH (i.e., IL-

of PCs (Flower and

effects of lipocortin

also relate to actions on arachidonic

acid release, CRH

or release, or other

mechanisms.

as yet unknown

Several other endogenous IL-1 actions, mental

and melanocyte

evidence

biologically

suggests

important

Cytokines

that

hormone,

these endogenous

often act synergistically,

growth factor-p

synthesis

vasoactive

stimulating

(see Kluger,

or actions of other cytokines. forming

could

peptides have been shown to modify

and for two of these, in particular,

tinal polypeptide

may act

intesexperi-

molecules

are

1991).

can all inhibit

IL-1 and stimulate

IL-lra

are the same in the brain is unknown.

which is now used clinically

is also believed to attenuate iting the actions

9.

BRAIN

Evolutionary

sclerosis patients,

of this condition

IN DISEASE

considerations

indicate that the synthesis and actions

to systemic

advantages.

inflammation,

changes,

probably

repair and recovery. Similarly,

serve to limit infection

neurotrophic

in brain neurones

of cytokine

synthesis

can prove detrimental

and protective

functions,

studies

ofinflammation of IL-l, TNF-ol, in

Syndrome,

sclerosis)

allergic encephalomyelitis, 1992). Increased

has also been observed including

patients,

multiple

sclerosis,

disease, and human

immunodeficiency

Although fascinating, such observations

disease,

in the development

virus infection

condition,

(Bauer

and Rothwell,

et

1995).

do not allow a clear distincwhich 1s usually of the

and a causal role of these molecules

ofthe disease. Several pieces of indirect evidence

the involvement

Alzheimer’s

brain Down’s

with some form of damage and/or inflammation expression,

used

lobe epilepsy, Parkinson’s

tion to be made between the effect ofthe condition, brain on cytokine

in

models

in many neurological

Alzheimer’s

temporal

ui., 1991; Selmaj et al., 1991; and see Hopkins

associated

cytokines

have suggested the involvement

and IFN-ol (see Panitch,

expression

disorders

have implicated

and similar studies on animal

(c.g., experimental

as a model of multiple

and behavioural

function. in rodents

acute neurodegeneration,

suppres-

lead to energy deficit

and wasting (cachexia), and prolonged somnolence Experimental

or in the brain

or even fatal. For example, chronic

impair neuronal

effects

sustained or severe

In the periphery

sion of appetite and elevated body temperature

cytokine

and

clearly have been demonstrated.

Hourever, as with many homeostatic activation

by

sleep,

to conserve valuable energy reserves, and to promote

of cytokines

support

Indeed,

disease that are mediated

actions in the brain, such as fever, HPA activation,

and behavioural

changes

by inhib-

1992).

in the brain must offer biological

many of the responses cytokine

(Panitch,

CYTOKINES

of cytokines

in multiple

symptoms

of IFN-a

of cytokines

(mainly

IL-1 and IL-6) in

disease, since they can induce classical features of thfa such as fl-amyloid precursor protein expression, synthesis

of acute phase proteins, Vandenabeele

and glial activation

and Fiers,

1991). In multiple

(Royston et ul., 1992; sclerosis,

studies on

animal models and the proven benefit of IFN-/3 therapy in patients provides

more direct

(Panitch,

1992).

support

The study of cytokine

actions

Many of the molecules

in the brain is still in its infancy.

described

have been discovered

the last few years, and their number rate. Nevertheless,

is increasing

it is now obvious

that

only in

at a remarkable

these

molecules

can

influence, either directly or indirectly, most aspects of CNS function. Understanding

of their importance

and their mechanisms

in physiology

and pathology

of action has been limited by the availability

of selective receptor antagonists,

which now are being eagerly sought

by biologists

in industry and academia. The potential

of cytokines

in many of the major neurological

only limited effective treatments

exist has given great importance

and impetus to research in cytokine potential

involvement

disorders for which

neurobiology.

role in the neural development

However, their

and function

of the brain

possibility.

but some inhibit the synthesis

synthesis in peripheral cells (Turner et ul., 1991; Vannier rt ul., 1992), IFN-0,

10. CONCLUSIONS

is also an intriguing

For example, IL-4, IL-lo, and trans-

but whether these properties

et al.

for the involvement

of cytokines

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Breder, C. il., Dinarello,

Receptors

in the Central

Nervous

System

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and Their

Receptors

in the Central

Nervous

System

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