Interleukin 1 induces a neurally mediated colonic secretion in rats: Involvement of mast cells and prostaglandins

Interleukin 1 Induces A Neurally Mediated Colonic Secretion in Rats: Involvement of Mast Cells and Prostaglandins VASSILIA THEODOROU,* and LIONEL BUENO* *Department France

of Pharmacology,

HELENE

EUTAMENE,*

JEAN FIORAMONTI,*

lnstitut National de Recherche Agronomique, Toulouse: and kstitut

Backgfound/Aims: lnterleukin lp (IL-lb) is known to regulate intestinal ion and water transport in vitro through prostaglandin release. This study investigated the effect of IL-Q on colonic net water flux in vivo to determine its nature (nerve mediation versus action on the epithelium), the mediators involved, and its relationship with mast cell degranulation. Methods: Isolated colonic loops of anesthetized animals were infused with Ringer’s buffer containing [14C]polyethylene glycol 4000. Net water flux was calculated according to 14C activity determined in the effluent collected at 15minute intervals. Histological analysis was used to identify intact mast cells in colonic sections and radioimmunoassay to determine histamine levels. Results: Both IL-lp and the calcium ionophore A23187 induced colonic hypersecretion during 30 minutes. This effect was blocked by tetrodotoxin, doxantrazole, and indomethacin but not chlorpheniramine. Recombinant human interleukin lb decreased the number of intact mast cells. This effect was eliminated by doxantrazole but not tetrodotoxin or indomethacin. A23187 or IL-@ increased histamine levels in the effluent during 75 and 45 minutes, respectively. Conclusions: In vivo, rhllp induces colonic hypersecretion in rats. This effect is nerve mediated but not Hi receptor mediated and involves mast cell degranulation and prostaglandin release.

I

nterleukin

1 (IL-l)

JEAN L. JUNIEN,?

is a cytokine

primarily

produced

by macrophages and monocytes.’ Two forms of IL-l, IL-la and IL-lp, are produced by two distinct genes.’

Indeed,

IL-l

intestinal

de Recherche Jouveinal, Fresnes,

and IL-3 have been reported

Cl- secretion

the production

of prostaglandins.6z7

In vivo studies

suggest that effects of IL-l on behavior,* ity,” and gastric

to stimulate

in the chicken and rabbit through

stasis”

are mediated

intestinal

through

also

motil-

the release

of prostaglandins. There is now considerable trolyte

movements

through

regulated

by neuroimmune

immune

cells (neutrophils,

macrophages)

evidence

located

the intestinal reactions.

in the lamina

association

as bidirectional

with

the nervous system.”

nerve endings sensory

substances

including

and

and submuand

and may act agents

Mast cell degranulation

of stimuli

endogenous

basophils,

propria

are

the various

by close anatomical

communicating

by a variety

mucosa

Among

eosinophils,

cosa, mast cells are characterized functional

that fluid and elec-

within

is triggered

nerve

stimulation,‘”

such as cytokines

or neuropep-

tides,

or exogenous

substances

cium

ionophores,‘3

leading

such as antigens

or cal-

to the release of mediators

such as histamine, prostaglandins, or serotonin, which are known to affect intestinal ion transport.‘4X’5 Therefore, arachidonic

acid metabolites

lipo-oxygenase intestinal

pathways

inflammatory

of both cycle-oxygenase

are diarrhea-inducing diseases.‘”

Also,

and

agents

in

a relationship

between IL-l, basophils, and mast cell degranulation has been shown in vitro,” and a direct interaction between this cytokine However,

and neural membranes the effect of IL-lp

is now suggested.18

on colonic

secretory

re-

Both recognize

the same receptor

and exert quite similar

sponse has never been explored in vivo in the presence of extraintestinal circuits. The mediators involved and

and extremely

broad

effects,

the relationship

biological

including

host

immune defense reactions,* synergism with other cytokines,’ and proinflammatory activity.3,4 Recent studies have shown that IL-l production is enhanced in animal models of intestinal inflammation’ as well as in tissue specimens and cell preparations from patients with inflammatory bowel diseases* and parasitic diseases.5 In vitro studies have proposed that cytokines have a regulatory role on intestinal water and ion transport.

with mast cell degranulation

remain

un-

known. Consequently, the present study was undertaken to determine the effect of IL- 10 on colonic water absorption in the anesthetized rat. Among the mechanisms Abbreviations used in this paper: ED=, median effective dose; IL, interleukin; rhll-1, recombinant human interleukin 1; TXX, tetrode toxin. 0 1994 by the American Gastroenterological Association OOl6-5085/94/$3.00

1494

THEODOROU

involved,

GASTROENTEROLOGY

ET AL.

we investigated

mediators

the role of mast

and determined

of IL-lp

is neurally

whether

cells and some

the secretory

action

collected

mediated.

period

Materials and Methods Histological Forty divided

male

received

kg intravenously sis inhibitor, 5 pg/kg

10 mg/kg

IP. Animals junction)

in Carnoy’s solution

5 /.rg/

cell stabilizing

a prostaglandin

were killed

were collected.

were cut at a thickness

synthe-

Specimens

mast cells per animal

were fixed

with

Three sections

microscopy,

intact mast cells was counted

after

colon (3 cm from

of 5 pm and stained

by light

before

30 minutes

toluidine

for each ani-

and the number

for each section.

of

The number

was the mean value obtained

of for

three sections.

housed

release measurement.

and

fed

with

3 groups were used

Animals

laboratory

g)

pellets

of the colonic --I yL.crn . h-‘. Water

performed

fluxes occurring

as previously

(2 g/kg IP), a midline

described.‘” laparotomy

was performed

A S-cm segment

colon at 3 cm from the cecocolonic extremities

and cannulated

segments

polyethylene

anesthesia

in all animals of the proximal

was ligated at its perfusion.

and replaced

Cannu-

in the abdominal

was closed, and the rats were placed on

pads to maintain

throughout

junction

for intraluminal

were rinsed

cavity. The abdomen

Under urethane

their body temperature

each experiment.

In addition,

glycol permeation

around 37°C

the animals in which

levels were measured

ted with a small silicone catheter into the right jugular vein.

(0.9-mm

were fit-

diameter)

inserted

30-minute negative

periods.

Positive

values indicate in rats receiving

Another

Mg2+,

1.2;

Ca2+,

1.3;

HCOs-,

25.0;

HPO**-,

17.0;

HzPOd-, 0.3; and glucose, 5.0. The solution also contained 1 lCi/L of E’*C~polyethylene glycol (mol wt, 4000) as nonabsorbed dilution marker of water flux and 5 g/L of unlabeled

in-

net absorption;

of water.

period, values of net water flux as

(1, 3, and 5 pg/ in three groups

treatment

with

a histamine

(5 pg/kg

TTX

of

(5 pg/kg

(10 mg/kg

H1 receptor

on net water movement IP). The effect

kg IP), TTX (5 pg/kg chlorpheniramine

IP),

antagonist

20, 120, 20, and 20 minutes

indomethacin,

in five groups

either

IP), indomethacin

(1

before

changes induced

of calcium

ionophore

alone or preceded

and chlorpheniramine

by TTX, was deter-

of animals.

The effects per se on net water flux of doxantrazole

groups

in

saline (0.3 mL) were considered

(5 mg/kg

administered

by rhIL-lp

(cm)

series of four groups were used for evaluating

IV), doxantratole mg/kg),

minute

15-minute

values represent

kg IP) on net water flux was determined animals.

per

flux is expressed

basal net water flux values. Effect of rhIL-lb

IV), indomethacin

(1 mg/kg)

(10 mg/kg

were evaluated

(5 mgi IP), and

in four distinct

of animals.

Two supplementary eventual

permeation

the intestinal

groups

of animals

of [‘*C]polyethylene

were used to test glycol 4000 across

wall. One group received saline (0.3 mL IP) and

the second rhIL- 1 p (5 /.tg/kg IP). Blood samples (0.5 mL) were taken from the jugular vein at l-hour equilibration

period,

indomethacin,

were purchased

from Sigma

after a 2-hour

of 240 minutes.

No

in the blood of each rat during

was kindly provided TTX,

by Dr. Mermod

(Glaxo, Swit-

chlorpheniramine,

and A23 187

Chemical

and doxantrazole was a gift of Wellcome (Beckenhan, England).

Histamine

intervals

over a total period

radioactivity was detectable the whole time course. rhIL-lp

After cleansing and elimination of contents with warm saline, the colonic loops were infused with Ringer’s buffer solution containing (in mmol/L): Na+, 142.6; K+, 5.0; Cl-

in buffer solution

a mean net flux of water over

net secretion

After a 2-hour equilibration obtained

zerland);

Net Water Flux Measurement

Flux,

over two consecutive

to obtain

(U.A.R.,

were

formula:

L is the length

and net water

doxantrazole,

studies using isolated loop techniques

to expose the large intestine.

123.8;

segment;

tervals were averaged

mined

In vivo transport

samples

flux for each

as counts

of perfusion;

were individually Epinay,

in collected

by the following

expressed

A23 187 (5 mg/kg IP) administered

France).

over a total

Water

P X L = Net Water

respectively,

rhIL- 1 p, respectively,

for histamine

heating

effluent,

Seventeen

rats (250-300

‘*C activity scintillation.

in which cpmS and cpmX are the i4C activity and

or chlorpheniramine,

of 8 male Wistar

periods

cpmX

Animal Preparation for Net Water Flux and Histamine Release Measurement groups

segment

the first 2 hours corresponding

was calculated

the effect of previous

were used for net water flux determination;

lated

period.

(cpm); P is the rate #L/h)

in paraffin blocks. Sections

blue and/or alcian blue-safranin.

intact

a mast

of proximal

and mounted

mal were analyzed

lp (rhIL-

(TTX),

IP, 20, 120, and 20 minutes

and tissue samples

the cecocolonic

interleukin

tetrodotoxin

IP; and indomethacin,

rhIL-lp

treatment,

human

received

15-minute

with

1 - cpmS

The colonic

No. 6

(6 mL/h), and the effluent was

consecutive

interval

g were

Eight control rats received

(IV); doxantrazole,

agent, 5 mg/kg

250-300

as a carrier. rate

by liquid

(IP). A second group of animals

5 pgg/kg recombinant

l/.3). Three other groups

during

15-minute

into 5 groups of 8 animals.

4000

of 240 minutes,

was determined

rats weighing

0.3 mL saline intraperitoneally

glycol

to the equilibration

Methods Wistar

polyethylene

was infused at a constant

Vol. 106,

Co. (St. Louis, MO); Research Laboratories

Release Assay

Animals prepared as described above underwent infusions with a Ringer’s solution buffer at a constant rate (6 mL/ h). After a S-hour equilibration period, histamine concentra-

INTERLEUKIN 1 AND COLONIC SECRETION

June1994

Table 1. Number of Submucosal

Intact Mast Ceils Identified in the Proximal Colon After rhll-lb Without Previous Administration of TTX, Doxantrazole, and lndomethacin

No. of intact mast cells

Saline (0.3 mL IP) 15.5 k 0.8

Administration

1495

With or

l-l-x

Doxantrazole

lndomethacin

(5 clg/kg IP)

(5 clg/kg IV) + rhll-lb

(5 mg/hg IP) +rhlL-1P

(10 mg/kg IP) +rhlL-1P

5.0 2 2.2”

3.4 2 1.7”

12.8 2 3.3

3.9 2 1.1”

rhll-1P

NOTE. Results are expressed as means k SD: n = 8. %ignii’kantly different (P -c 0.01) from control values.

tions in the effluent collected during consecutive 15-minute periods over a total period of 90 minutes were measured by a histamine radioimmunoassay*’ using monoclonal antibodies (Immunotech, Marseille, France). The limit of detection for the assay is 0.2 nmol/L. The intra-assay and the interassay coefficients of variation for this method are <8% and < 1 l%, respectively. Eight control animals received saline (0.3 mL IP). The second and third group of rats received calcium ionophore A23187 (5 mg/kg IP) and rhIL-lfi (5 pg/kg IP), respectively. Histamine levels were measured in the effluent collected during a 15-minute period before treatment and in effluents collected during five consecutive 15-minute periods after different treatments.

kg IP) administration and 41.1 controls, increased

Results

nificantly controls

submucosa

increased

up to 45 minutes

levels were

1). rhIL-1 p sig-

levels in comparison

+ 26.3 nmol/L) after A23187

dur-

strongly

its administration

later (Figure

histamine

1). In

in the effluent dur-

following

its administration. than

A23187

and high histamine

up to 75 minutes (140.9

following nounced

period

2 9.9,

(Figure

quite unchanged

In contrast,

concentration

+ 25.5 nmol/L),

observed

12.5, 45.5

during

This

effect was less pro-

increase

later (Figure

with

the 15 minutes and was observed

1).

Control. Basal net water flux was +40.7 pL.crn-’

. h-l.

3 and 5 pg/kg net secretion

IP administration reversed

of rhIL-lp

the net water absorption

for 30 minutes

in a dose-dependent

+ 54.2

at doses of into a manner.

A dose of 1 pg/kg was ineffective, and the median effective dose (ED,,) of rhIL-lp was 2.2 pg/kg (Figure 2B).

Mast Cell Degranulation and treated

levels remained

the histamine

ing the 15-minute (439.8

f

respectively

influence of rhll-1P on Net Water Flux

Values of net water flux obtained after a 2-hour equilibration period were expressed as means + SD over 30-minute periods from 60 minutes before to 60 minutes after treatment. Results were analyzed by Student’s t test for unpaired data.

Histological

histamine

were 40.9 nmol/L,

ing the time course study.

Statistics

control

+- 10.1

The 5 pglkg-dose

analysis

showed

animals

were located

near blood

that

vessels and nerves.

mast

of rhIL-lp

induced

a strong net water

cells of

in the colonic The number

of intact mast cells counted in sections of control animals was 15.5 + 0.8. In contrast, the number of intact mast cells in the rhIL-1 P-pretreated (5 pg/kg) significantly (P < 0.01) decreased (Table

animals was 1). TTX (5

pg/kg IV) and indomethacin (10 mg/kg IP) administered before rhIL-1 p did not prevent the rhIL-1 P-induced mast cell degranulation; the number of intact mast cells counted in the respective sections remained reduced and significantly different (P < 0.01) from that of the control mast cells (Table 1). Only doxantrazole (5 mg/kg IP) administered before rhIL- 1 p prevented the rhIL- 1 p-induced mast cell degranulation; the number of intact mast cells was similar (12.8 ? 3.3) with control mast cell number (Table 1). Histamine levels detected in the effluent before saline (0.3 mL IP), A23187 (5 mg/kg IP), and rhIL-lfl (5 pgl

Flgure i. Time course effect of A23187 and rhll-1P on histamine release in the colonic effluent (means rt SD; n = 8). ?,?control; a, A23187 (5 mg/kg IP); ?,? rhll-1B (5 pg/kg IP). *Significantly different (P < 0.05) from controls and ‘from rhll-1P values.

1496

secretion tion;

GASTROENTEROLOGY Vol. 106, No. 6

THEODOROU ET AL.

during

values

cantly

the 30 minutes

(-75.2

different

2A). However, pg/kg

?

46.8

(P <

following

pL.crn.h-’

0.01)

from

IP), the net water flux was restored,

were positive significantly

(+29.9 different

+ 67.5

Effects of TTX, doxantrazole,

(5 pg/kg

TTX

(5 pg/kg

indomethacin,

(10 mg/kg

after administration

(5 pg/kg

on Net Water

Loops

Flux

in Anesthetized

Net water flux (~LL.~rn~~~h~‘)

and not

IV) given

IP) suppressed

and

IV), doxantrazole

of rhIL-1 p had no

flux determined

(Table

(5

IP), and chlorphen-

IP) in the absence

effect per se on the net water minutes

Colonic

O-30

mina

30-60

mina

(P > 0.05) from basal values (Fig-

TTX chlorpheniramine. mg/kg IP), indomethacin (1 mg/kg

in Isolated

because values

~L.cm-‘~h-‘)

Indomethacin,

and Vehicles

Rats

(5

ure 2A).

iramine

Obtained

(Figure

after rhIL-lb

of TTX, Doxantrazole,

Chlorpheniramine,

were signifi-

basal values

from 30 to 60 minutes

Table 2. Effects

administra-

for 60

2).

20 minutes

rhIL-1 P-induced

Saline (0.3 mL IP) TTX (5 ug/kg IV) Doxantrazole (5 mg/kg IV) lndomethacin (10 mg/kg IP) Chlorpheniramine (1 mg/kg IP)

+39.2 +53.8 +42.4 i32.3 +48.4

2 2 2 ? ?

41.3 48.2 51.2 34.6 32.9

+34.6 +28.4 +50.3 +42.3 +39.1

2 2 2 rt 5

36.7 38.7 29.9 31.7 29.9

NOTE. Results are expressed as means 2 SD; n = 8. “Time corresponding to periods of measurement after rhll-16 in other series.

before rhIL-lb net secretion

(+22.7

? 19.0 lL.crn-‘.

net water

flux values

lp administration

h-‘) obtained

(Figure

3). Furthermore,

60 minutes

in TTX-pretreated

after rhIL-

animals

39.9 /.LL*cm-’ . h-*) were not significantly different

(+47.9 (P >

+

0.05)

from basal net water flux values.

Similarly, doxantrazole administered IP 120 minutes before rhIL- 1 p at a dose of 5 mg/kg eliminated the rhILlp-induced

colonic secretory

effect; values of net water

absorption (+50.2 ? 23.3 pL.crn-‘.h-‘) obtained 30 minutes after rhIL-1 p administration in doxantrazolepretreated

animals

were not significantly

(P >

different from basal values (Figure 3). Values 60 minutes after rhIL-lb in animals receiving -66

-36

0

30

60

administration of doxantratole 38.9 pL.crn-‘.h-‘).

time (mill)

t rhlL-18

(5 &kg

Animals

IP)

minutes

receiving

were normal

IP indomethacin

Control

m

rhlL-1B

(1 &kg

IP)

a

rhlL-18

(3 &kg

IP)

obtained previous (+52.3

?

(10 mg/kg)

20

before IP rhIL- 1 p (5 kg/kg) did not show colonic

ml

H

0.05)

rhlL-19 (5 Kg/k9 IP)

3 5o 3

= 2

0

3 s z

-50

1. *

m

rhlL-1R

(5 &kg

I

m

lndomethacin (19 m&9 +rhlL-19

IP) =

IP)

Chlorpheniramine (‘+~~~;‘)

FlgBre 2. (A) Time course study of colonic net water flux obtained before and after rhlL-16 at the maximal effective dose (5 ug/kg IP) on colonic net water flux in anesthetized rats (means f SD; n = 8). *Significantly different (P < 0.01) from control net water flux values. (B) Dose-related effect of IP rhlL-16 on net colonic water flux in anesthetized rats (means IT SD; n = 8). Note that rhll-16 at 3 ug/kg and 5 pg/kg induced a colonic hypersecretion during the 3Dminute period after its administration. *Significantly different (P < 0.01) from basal values.

Figure 3. Influence of lTX, doxantrazole, indomethacin, and chlorpheniramine administered 20, 120, 20, and 20 minutes before rhll16 administration, respectively, on net water flux in anesthetized rats (means 5 SD; n = 8). Note the suppression of rhll-la-evoked colonic hypersecretion by llX, doxantrazole, and indomethacin but not by chlorpheniramine during the 0-30-minute period after rhlL-16. *Significantly different (P < 0.01) from water flux values obtained when rhll-lb was administered alone.

INTERLEUKIN 1 AND COLONIC SECRETION

June 1994

1497

Effect of TTX, doxantrazole, indomethacin, and chlorpheniramine. TTX (5 Fglkg IV) given 20 minutes A 23157 (5 mslkg IW

before A23187

the secretory period after (P <

were significantly

values

Moreover,

obtained

during

ministration

‘5+E%l;)

IP) eliminated

administration from Doxantrazole

(5 mg/kg

effect of A23 187; values in the 0-30-minute with

different

A23187

alone

the 30-60-period

in TTX-pretreated

0.05)

(Figure

4).

after A23187

ad-

animals,

the net water

flux was normal.

m

lndomethacine ‘lo,~2~g’

Similarly, tin

Chlorpheniramine ‘1+ggg)

A23187

hypersecretion

during

1 p administration. jJL.crn-’

the 30-minute The

flux

oh-‘) in animals

methacin

values

previously

were not different

3). Also, rhIL-lp

period

after rhIL-

(+12.2 treated

from control

lr

36.4

with indo-

values (Figure

had no effect from 30 to 60 minutes

+38.5

previous

chlorpheniramine lp-induced

administration

(1 mg/kg

net water secretion

not significantly

different

the 30-minute

during

(P >

0.05)

this period from values

tained after rhIL- 1 p was given alone (Figure of rhIL-lp

was observed

rhIL- 1 p administration;

from

were ob-

3). No effect

30 to 60 minutes

after

net water flux values (+ 5 3.2 If:

were not 38.8 pL.crn-’ *h-l) (P > 0.05) from control values.

Effect of A23187

significantly

different

Control. A23 187 at a dose of 5 mg/kg IP reversed

cantly rhIL-lp

different

+ 39.8 pL.crn-‘.h-‘) (P >

0.05)

were not signifi-

from values

(5 pg/kg IP) administration

obtained

rt 13.6 pL.cm-‘.

during

the

O-

(+62.8

& 10.8 and

h-‘, respectively)

were not sig-

(P > 0.05) from basal values (Figure

after A23187

methacin-pretreated

was observed

in doxantrazole-

animals.

In contrast,

30-

and indochlorphenira-

mine (1 mg/kg

IP) given 20 minutes

before A23187

not antagonize

the A23187-induced

colonic hypersecre-

tion;

values

after (-86

A2 3 187 in chlorpeniramine-pretreated ? 62.3 PL. cm-’ . h-l) were not

different

obtained

(P >

0.05)

A23 187 alone (Figure

during

from

the 0-30-minute

flux values

4). The negative

restored

during

the 30-60-minute

(+37.9

+ 59.7 pL*cm-l.h-‘).

did

period animals

significantly obtained

after

water flux was

period after A23187

Dlseusslon This study

shows that

in vivo rhIL-lp

reverses the net water absorption

abruptly

in the proximal

colon

into a net secretion during a short (30-minute) period after its administration in a dose-dependent manner. The short

time

effect of IL-l

observed

in this

study

is in

agreement with studies in vitro showing that serosal addition of IL-l induces an increase of basal short-circuit current

in the ileum

during

30 minutes

in rats” and in


on Net Water Flux

(P < 0.01) the net water absorption into a net secretion during the 30-minute period after its administration; values (-89.6

A23187

60 minutes

of

the values of flux obtained

h-l)

+ 56.2 fl.crn-‘.

during

after

before

colonic hyper-

obtained

of the effect of A23187

IP) failed to reverse the rhIL-

period after rhIL-1 p (5 pg/kg); (-59.1

(20 minutes)

values

period different

20 minutes

the A23187-induced

because

nificantly

IP) and indometha-

120 and

4). Absence

after administration. In contrast,

(5 mg/kg

IP) given

suppressed

secretion, 30 minute

figure 4. Influence of A23187 (5 mg/kg IP) on colonic net water flux and antagonism of this effect by TTX, doxantrazoie, indomethacin, and chiorpheniramine administered 20, 120, 20, and 20 minutes before, respectively, A23187 administration in anesthetized rats (means -c SD; n = 8). Note that A23187 induces a short (3Cminute) coionic hypersecretion; TTX, doxantrazoie, and indomethacin but not chiorpheniramine suppressed this effect. *Significantly different (P < 0.01) from water flux values obtained when A23187 was administered alone.

doxantrazole

(10 mg/kg

after

(Figure 4). The neg-

ative net water flux was restored during the 30-60period after A23187 (+45.6 2 31.2 pL.crn-‘.h-‘).

glycol4000 can be absorbed during periods of increased mucosal permeability. Because no ‘*C radioactivity was detected in blood after rhIL-1 p administration, this water soluble marker seems suitable in our model. Secondly, we used rhIL-lp in the rat. However, rhIL-lp has been already used in other rat models,8,9 and there is homology between polypeptides coded by IL-l genes in different species.**

1498

THEODOROU

The

GASTROENTEROLOGY

ET AL.

rhIL- 1 P-induced

eliminated

colonic

by pretreatment

cell stabilizing

secretory

with

agent, suggesting

serotonin,

in the colonic

eicosanoids, secretory

ported by histological

was

a mast

that one or several me-

diators released by mast cell degranulation mine,

effect

doxantrazole,

or IL-l

effect of IL-lb.

examination

such as hista-

itself are involved This was sup-

indicating

a dramatic

(67%) decrease of intact mast cells in the colonic submucosa after measured

rhIL-1 p administration. in this study

degranulation

Histamine

is frequently

used as a mast cell

criterion23324 because histamine

be a specific mediator lp-induced

level increase

the hypothesis

on mast cells. Moreover,

doxantrazole

in the colonic

ef-

was able to prevent

rhIL-lp-induced

mast cell degranulation,

on mast cells. Furthermore, reported

rhIL-

of a direct action of IL-l

action of rhIL-lp nian and Brav”

appears to

of mast cells.25 Furthermore,

histamine

fluent enhanced

release

confirming

that a relatively

an

Subrama-

low concentra-

that did not show a neural involvement chloride

secretion

esis that IL-lb

in rabbit ileum.

may act directly

supported

by the observation

suppresses

noradrenaline

synaptosomes

that

from

exogenous

rat

jejunal

myenteric

the

secretory

plexus.22 Similarly, A23187,

TTX

suppressed

suggesting

a neuronal

of mediators

with other studies

ment of intramural in the ileum.

nerves in the regulation

of ion trans-

For example,

chloride

secretion,

in preparations

indicating

from TTX-sensitive

a role of transmitters cells present

propria.30

effects directly

indirectly.

Chlorpheniramine

failed

lb-induced

or at least H, receptor subtype

on basophils

lb-induced

of the divalent

A23187

suggested

that histamine

a similar

intestinal

chloride

induces

effects on Na+ and Cl-

tively similar

manner

dent mechanism.28 mast

it has been shown transport

to those of IL-l

that A23187

the enterocyte

in a qualita-

lation of arachidonic

by a Ca*+-depen-

A23187, which is known to induce l3 induces a strong and long-

cell degranulation,

lasting histamine level increase in the effluent. A single administration of another mast cell degranulating compound

48180

is followed

by an increase

of histamine

stimulation.32

flammatory

We also provide evidence that the rhIL-lb-induced colonic secretory effect is eliminated by previous administration of TTX, suggesting a neuronal mediation of this effect. However, TTX did not prevent the rhIL-lpinduced mast cell degranulation, suggesting that the involvement of the neuronal component in the IL-lpinduced colonic secretory effect is distal to mast cell. This in vivo observation contrasts with previous results’

mediators

is released

on

nerves released

in high levels for

diarrhea

affecting

fluid

and

ion transport

through

stimulation of prostaglandin production and ena role of serotonin in the teric nerves.15,33 Accordingly,

colonic secretion

ionophore acts as a mast cell degranulator in this study and suggesting the involvement of corresponding mediators released in the secretory effect.

action

via stimu-

7 hours or more after administration of the degranulating Serotonin also contributes to in48180 compound.29

TTX

cell degranulation. Doxantrazole also eliminated the secretory effect of A23187, confirming that this calcium

studies

and enteric

the numerous

from mast cells, serotonin

in the IL-

by increasing

a direct

acid metabolism

Among

release from isolated peritoneal

histamine release from isolated mucosal mast cells. Accordingly, we can speculate that the secretory effect observed is related to peritoneal rather than mucosal mast

diarrhea

through

the rhIL-

previous

via Hi receptors31 or indirectly

during a 60-90-minute period.29 Moreover, Pearce et a1.24 also showed that A23 187 induces a 82.4% histamine rat mast cells and a 24%

induces

secretion

or

that histamine

is not involved

secretory effect. In contrast,

ionophore

Besides,

to block

effect, suggesting

the secretory effect of rhIL-1 p during

short period.

cation

in the submu-

many of mast cell

from human basophils and adenoidal mast cells in a dosedependent manner in vitro. However, this rhIL-1 action

reproduces

origi-

However, secretory

secretory

from

colitis, TTX was able to prevent

induce

ministration

This is

the involve-

with ulcerative

cosa and lamina

of

proposing

patients nating

effect

in the action

released by mast cell degranulation.

in agreement port

involvement

released

by others.26.27 Ad-

rhIL-lb release by

mediators

has not been confirmed

the hypothnerves is also

acetylcholine

release

tion of rhIL- 1 was able to induce direct histamine

No. 6

in IL- 1 -induced

However, on enteric

and/or

prepared

Vol. 106,

administered

induced

by IL-lb

can not be excluded.

alone does not modify

colonic

basal

net water flux. This suggests that a neuronal component is only involved in stimulated secretion. In vitro studies in rat and dog colon have also shown that TTX induces little or no change in residual net ion flu~.~**~’ In this study,

the effects of rhIL-lp

and A23187

on

colonic water movements were eliminated by indomethatin, a prostaglandin synthesis inhibitor, suggesting a prostaglandin mediation. However, indomethacin did not block the effect of rhIL-lp on mast cell degranulation, suggesting a prostaglandin involvement distal to the mast cell. This result agrees with those in in vitro studies, suggesting that the effects induced by IL-1 in the chicken and rabbit ileum are also mediated by prostaglandins. Furthermore, fibroblasts from the T84 cell line pretreated with IL-1p induce a greater chloride secretion in response to stimulation with bradykinin and

INTERLEUKIN 1 AND COLONIC SECRETION

June 1994

histamine,

most likely as a result of enhanced

din production.‘*

Infusion

lates prostaglandin hanced

of the colon with IL-l

tissues.36

The

intestinal

effects of prostaglandins

are classically

mediated

of adenylate

by stimulation

tion of enterocyte

3’ 5’-cyclic However,

neural sites, releasing

Accordingly, ofprostaglandin

Ionic hypersecretion

we

is distal

that

the co-

regarding

cells and/or

the level,

mesenchymal

or on nerve endings.

Finally,

we conclude

transient

colonic

neurally

mediated nervous

movements

that rhIL-1 induces

hypersecretion and underlines system

but depends

release of mediators,

states.

a drastic

effect is

the important

role of

of colonic

Moreover,

is not mediated

water

the secre-

by a H, receptor

on mast cell degranulation particularly

but

in vivo. This

in the control

in pathological

tory effect of rhIL-lp subtype

suggest

ace-

to mast cell degranulation;

i.e., direct action on epithelial

enteric

can also act on

E2 in rhIL-lp-induced

however, we can not make conclusion elements

to be

particularly

can

ogy of the gastrointestinal tract and liver. In: Heyworth G, ed. New York: Raven, 198865-91. 14. Nasserman SI, Barrett KE. Huott PA, Beuerlein HG, Kagnoff MF. Dharmsathaphorn EA. Immune related Cl- secretion. I. Effect of histamine on the T 84 cell line. Am J Physiol 1988;254:521532. 15.

Hirose R, Chang EB. Effects of serotonin on Na/H exchange and intracellular calcium in isolated chicken enterorytes. Am J Physiol 1988; 254:G891-G897.

16.

Rampton DS, Hawkey CJ. Prostaglandins Gut 1984; 25:1399-1413.

monophosphate

prostaglandins

involvement

secretory

considered

neurotransmitters,

tylcholine.3s

was en-

cyclase and eleva-

adenosine

13. Barret KE, Metcalfe DD. Mucosal mast cells and IgE. In: Immunol-

stimu-

E2 release; this stimulation

in inflamed

concentration.37

prostaglan-

and the

1. Dinarello CA. Interleukin-1 and its biologically related cytokines. Adv lmmunol 1989;44:153-191. 2. Durum SK, Schmidt JA, Oppenheim JJ. Interleukin-1: an immunological perspective. Annu Rev lmmunol 1985;3:263-287. 3. Morteau 0, Pons L, Bueno L. Platelet-activating factor and interleukin-1 are involved in colonic dysmotility in experimental colitis in rats. Gastroenterology 1993; 104:47-56. 4. Nakamura M, Saito H, Kasanukil J, Tamura Y, Yoshida S. Cytokine production in patients with inflammatory bowel disease. Gut 1992; 7:933-937. 5. Dinarello CA. Interleukin-1 and pathogenesis of the acute phase response. N Engl J Med 1984;311:1413-1418. 6. Chang EB, Musch MW, Mayer L. Interleukins 1 and 3 stimulate anion secretion in chicken intestine. Gastroenterology 1990; 98:1518-1524. 7. Chiossone DC, Simon PL, Smith PL. Interleukin-1 effects on rabbit ileal mucosa ion transport in vitro. Eur J Pharmacol 1990; 180:217-228. 8. Crestani F, Seguy F, Dantzer R. Behavioural effects of peripherally injected interleukin-1: role of prostaglandins. Brain Res 1991; 542:330-335. 9. Fargeas MJ, Fioramonti J, Bueno L. Central action of IL-1 on intestinal motility in rats: mediation by two mechanisms. Gastroenterology 1993; 104:377-383. 10. MC Carthy DO, Daun JM. The role of prostaglandins in interleukinl-induced gastroparesis. Physiol Behav 1992; 52:351-353. 11. Bienenstock J. Implications of our understanding of gastrointestinal physiology. In: Neuroimmuno physiology of the gastrointestinal mucosa. Volume 664. 1st ed. New York: New York Academy of Sciences, 1992:1-g. 12. Dimitriadou V, Buzzi MG, Moskowitz MA, Theoharides TC. Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells. Neuroscience 1991;44:97-112.

and ulcerative colitis.

17. Subramanian N, Brav M. Interleukin-1 releases histamine from human basophils and mast cells in vitro. J lmmunol 1987; 138:271-275. 18. Collins SM, Hurst SM, Main C, Stanley E, Khan I, Blennerhassett P, Smain M. Effect of inflammation on enteric nerves. Cytokineinduced changes in neurotransmitter content and release. In: Neuro-immunophysiology of the gastrointestinal tract. Volume 664. 1st ed. New York: New York Academy of Sciences, 1992:415-424. 19. Quito FL, Brown DL. @ala’, met5)-enkephalinamide: CNS-mediated inhibition of prostaglandin-stimulated intestinal fluid and ion transport in the rat. Peptides 1987;8:1029-1033. 20. McBride P, Bradley D, Kaliner M. Evaluation of a radioimmunoassay for histamine measurement in biological fluids. J Allergy Clin lmmunol 1998;82:638-646. 21.

prostaglandins.

References

1499

Li YF, Weisbrodt NW, Moody FG. Effects of interleukin-16 on muscle and epithelial functions of the ileum in rats. Gastroenterology 1992; 102:A475.

22. Dinarello CA. Interleukin-1. Dig Dis Sci 1988;33:25-35. 23. Cocchiara R, Albeggiani G, Di Trapani G, Lampiasi N, Rizzo F, Geraci D. Modulation of rat peritoneal mast cell and human basophil histamine release by oestrogens. Int Arch Allergy Appl Immunol 1990;93:192-197. 24. Pearce FL, Befus A, Gauldie J, Bienenstock J. Mucosal mast cells. II. Effects of anti-allergic compounds on histamine secretion by isolated intestinal mast cells. J lmmunol 1982;128: 2481-2486. 25. McKay D, Perdue MH. Intestinal epithelial function: the case for immunophysiological regulation. Cells and mediators. Part 1. Dig Dis Sci 1993;38:1377-1387. 26. Younger RE, and Feeerrod HG. Characterization of mononuclear cell-derived histamine release enhancing factor. J Allergy Clin lmmunol 1987;80:547-557. 27.

28.

29.

30.

31. 32. 33.

34.

Massey WA, Randal TC, Kagey-Soboktkas A, Warner JA, Mac Donald S, Gillis AC, Allison YAC, Lichtenstein LM. Recombinant human IL-lo and b potentiate IgE-mediated histamine release from human basophils. J lmmunol 1989:143:1875-1880. Bolton JE, Field M. Ca ionophore-stimulated ion secretion in rabbit ileal mucosa: relation to actions of cyclic AMP and carbamylcholine. J Membr Biol 1977;35:159-164. Takeuchi K, Ohtsuki H, Okabe S. Pathogenesis of compound 48/ 80 induced gastric lesions in rats. Dig Dis Sci 1986;31:392400. Hubel K, Shirazi S. Human ileal ion transport in vitro: changes with electrical field stimulation and tetrodotoxin. Gastroenterologv 1982;83:63-68. Hardcastle J, Hardcastle PT. The secretory actions of histamine in rat small intestine. J Physiol (London) 1987;388:521-532. Cooke HJ, Nemeth PR, Wood JD. Histamine action on guinea pig ileal mucosa. Am J Physiol 1984;246:G372-G377. Cooke HJ, Carey HV. Pharmacologic analysis of 5-hydroxytryptamine action on guinea pig ileal mucosa. Eur J Pharmacol 1985;111:329-337. Andres H, Bock R, Bridges RJ, Rummel W, Schreiner J. Submuco-

1500

35.

36.

37.

38.

THEODOROU ET AL.

sal plexus and electrolyte transport across rat colonic mucosa. J Physiol (London) 1985; 364:301-312. Rangaghari PK, McWade D. Epithelial and mucosal preparations of canine proximal colon in Ussing chambers: comparison of responses. Life Sci 1986;38:1641-1652. Cominelli F, Nast CC, Gentilini P, Zipser RD. Recombinant interleukin-1 induces colonic prostaglandin production: lymphokines may have an important role in colitis (abstr). Gastroenterology 1988; 94:A75. Musch MW, Field M, Miller RJ, Stuff JS. Homologue desensitization to prostaglandins in rabbit ileum. Am J Physiol 1987; 252:GI20-G127. Bern MJ, Sturbaum CW, Karayalcin SS, Berschneider HM, Wachsman JT, Powell DW. Immune system control of rat and rabbit

GASTROENTEROLOGY Vol. 106, No. 6

colonic electrolyte transport: role of prostaglandins nervous system. J Clin Invest 1984;83:1810-1820.

and enteric

Received July 26, 1993. Accepted January 17, 1994. Address requests for reprints to: Lionel Bueno, Dr.Sc., Department of Pharmacology, lnstitut Natlonal de la Recherche Agronomique, 180 chemin de Tournefeuille BP 3, 31931 Toulouse, France. Fax: (33) 61-28-5310. This work was presented in part at the annual meeting of the American Gastroenterological Association in Boston, Massachusetts, May 1993, and has appeared in abstract form (Gastroenterology 1993; 104:A264). The authors thank P. Marche for skillful technical assistance.