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1 Institut National de la Recherche Agronomique-Institut National de la Santé et de la Recherche Médicale Unité 394, Neurobiologie Intégrative, 33077 Bordeaux, France; and 2 Laboratory of Immunophysiology, Department of Animal sciences, University of Illinois, Urbana, Illinois 61801
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study was designed to determine the role of
endogenous brain interleukin (IL)-1 in the anorexic response to
lipopolysaccharide (LPS). Intraperitoneal administration of LPS
(5-10 µg/mouse) induced a dramatic, but transient, decrease in
food intake, associated with an enhanced expression of proinflammatory
cytokine mRNA (IL-1
, IL-6, and tumor necrosis factor-
)
in the hypothalamus. This dose of LPS also increased plasma levels of
IL-1. Intracerebroventricular pretreatment with IL-1 receptor
antagonist (4 µg/mouse) attenuated LPS-induced depression of food
intake and totally blocked the LPS-induced enhanced expression of
proinflammatory cytokine mRNA measured in the hypothalamus 1 h after
treatment. In contrast, LPS-induced increases in plasma levels of
IL-1 were not altered. These findings indicate that endogenous brain
IL-1 plays a pivotal role in the development of the hypothalamic
cytokine response to a systemic inflammatory stimulus.
hypothalamus; lipopolysaccharide; interleukin-1; receptor antagonist; food intake
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PROINFLAMMATORY CYTOKINES mediate the local
and systemic components of the acute-phase response. Interleukin (IL)-1
is one of the key cytokines for the development of the centrally
mediated signs of sickness, including depression of food intake and
food-motivated behavior (8, 28). Peripheral and central administration
of recombinant IL-1 decreases food intake in rats and mice (21, 26).
This effect is abrogated by pretreatment with the IL-1 receptor
antagonist (IL-1ra) (19, 25, 27). IL-1 is synthesized in the
hypothalamus, together with other proinflammatory cytokines including
tumor necrosis factor- (TNF-) and IL-6, in response to peripheral
inflammatory stimuli (11, 23). Proinflammatory cytokines act in a
network fashion at the periphery, meaning that each cytokine induces
its own synthesis and the synthesis of other cytokines that potentiate
or oppose its effects. The possibility that a similar network exists in
the brain has been suggested by time-course studies of the expression
of transcripts of proinflammatory cytokines in the brain in response to
peripheral administration of the cytokine inducer lipopolysaccharide
(LPS). Intraperitoneal administration of a behaviorally active dose of
LPS increases the expression of TNF- and IL-1 mRNA in the brain
within 1 h after the treatment, and 3 and 6 h later IL-6 and IL-1ra
mRNA are expressed (11, 23).
To determine whether endogenous brain IL-1 plays a pivotal role in
LPS-induced behavioral depression, we measured food intake and
proinflammatory cytokine mRNA expression in the hypothalamus of mice
that were treated by a peripheral injection of LPS and a central
injection of IL-1ra. To ensure that centrally injected IL-1ra blocked
exclusively brain IL-1, we measured circulating levels of IL-1.
We confirmed that LPS induced a decrease in food intake that was
accompanied by an increase in proinflammatory cytokine synthesis in the
hypothalamus. LPS-induced anorexia was partially blocked by central
administration of IL-1ra. LPS-induced cytokine mRNA expression in the
hypothalamus was fully blocked by IL-1ra, whereas increased plasma
levels of IL-1 were not affected.
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MATERIALS AND METHODS |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals and materials.
Seven-week-old male mice of the CD-1 (ICR) BR strain (Charles River),
weighing 30-35 g at the start of the experiment, were housed in
polypropylene cages in a room that was maintained at 23 ± 1°C.
Lights were turned on from 8 PM to 8 AM, and food and water were
available ad libitum except for food intake experiments. LPS
(Escherichia coli, serotype 0127:B8) was obtained from Sigma Chemical (St. Louis, MO). This serotype was used because it had been
demonstrated to reliably increase body temperature and metabolic rate
in the rat, despite the fact that the rat is relatively insensitive to
endotoxin (15). Recombinant mouse IL-1 and sheep antibodies to mouse
IL-1 were obtained from National Institute for Biological Standards
and Control (Potters Bar, UK). IL-1ra was obtained from Synergen
(Boulder, CO). pMus3 was a kind gift from D. Shire (Sanofi, Labèges, France). Avidin-horseradish peroxidase was purchased from Dako and RPMI and calf serum from GIBCO-BRL (Cergy Pontoise, France).
Surgery and treatments. The experiments were conducted according to Authorization for Practicals on Animals ethical standards for humane treatment of animals and the French legislation concerning animal experimentation.
For intracerebroventricular injections, a 23-gauge stainless steel guide cannula was inserted stereotaxically over the lateral cerebral ventricle 10 days before the experiment in mice anesthetized with a mixture of ketamine (1.8 mg/kg) and xylazine (12.2 mg/kg) at 10 ml/kg body wt ip, as previously described (6, 7). Coordinates for the guide cannula were 0.6 mm posterior to bregma, 1.6 mm lateral, and 2 mm below the skull surface at the point of entry. Cannulas were secured with two stainless steel screws and dental cement. Mice were allowed to recover for 1 wk before experiments were performed. Intracerebroventricular injections (2 µl) were made by gravity, after a 30-gauge needle was lowered in the guide cannula (6, 7). Mice were given an intracerebroventricular injection of saline or IL-1ra (4 µg/mouse) immediately followed by an intraperitoneal injection of saline or LPS (5 or 10 µg/mouse). Mice were killed by decapitation 1 h after the injection (n = 5 for each experimental group), and the hypothalamus was rapidly dissected and frozen at
80°C until
use for RT-PCR. Blood was collected on ice in 10 U/ml endotoxin-free
heparin, and plasma was stored at 80°C until determination
of IL-1 concentrations by ELISA. The 1-h delay was selected on the
basis of the time-course experiment showing the induction of IL-1,
TNF-, and IL-6 mRNAs in the hypothalamus of mice injected
intraperitoneally with LPS (22). Doses of LPS and IL-1ra were selected
on the basis of previous experiments showing that 5 and 10 µg of LPS
reliably induce sickness behavior and proinflammatory cytokine mRNA
expression in mice (3, 22, 23) and 4 µg of IL-1ra fully block the behavioral effects of IL-1 (unpublished data).
Experimental design and food consumption measurement. Mice were randomly allocated to two experimental groups receiving intracerebroventricular IL-1ra (4 µg/mouse, n = 7) or saline (n = 5) treatments. In each experimental group, the animals were used as their own control and intraperitoneally injected with LPS (5 µg/mouse) or saline in a randomized order immediately after the intracerebroventricular treatment. For the measurement of food intake, mice were provided with a food pellet placed on the floor of their home cage. Cumulative food intake was measured by weighing food (precision 0.1 g) before the injection and at 2, 4, 8, 12, and 24 h after injection.
Semiquantitative RT-PCR analysis of hypothalamic cytokine
transcripts.
Total cellular RNA extraction was performed with a kit (RNA Now,
Biogentex, Seabrook) following the manufacturer's instructions. After
RNA extraction, 2 µg of purified total RNA were used for reverse
transcription in 20 µl. For PCR amplification, 0.5 µl (2-microglobulin) and 3 µl (cytokines; for sequences
of the primers see Ref. 22) of the cDNA of each sample were used.
Thirty cycles of amplification were used to amplify
2-microglobulin, IL-1, IL-6, and TNF- (1 min at
94°C, 1 min at 60°C, 1 min at 72°C) in the presence of
[-32P]dCTP (Amersham, 3,000 Ci/mmol) and an
internal control (pMus3). pMus3 (10 pg/amplification) was calibrated to
be used in the same amount for the coamplification of cytokines and
2-microglobulin performed in the same conditions (data
not shown). PCR products of proinflammatory cytokines and
2-microglobulin did not reach a plateau in the
conditions used (30 cycles, pMus 10 pg/amplification). Twenty
microliters of cDNA products were separated according to size. The
amount of radioactivity incorporated was quantified with a
PhosphorImager (Molecular Dynamics). To compare the expression of
cytokine mRNAs in the different experimental groups, results were
expressed as the ratio of cytokines per insert to
2-microglobulin per insert × 100.
Plasma IL-1 measurement by ELISA.
Plasma levels of IL-1 were determined by ELISA, as previously
described (22). Briefly, blood was collected on ice in 10 U/ml
endotoxin-free heparin (Sigma Chemical). Microtiter plates were coated
with sheep antibody to mouse IL-1 (2 µg/ml in PBS, pH 7.2, at
4°C). After addition of samples and standards (recombinant mouse
IL-1, 1.9-1,000 pg/ml) diluted in PBS with 0.5% BSA, plates were incubated for 24 h at 4°C, and the secondary biotinylated antibody to mouse IL-1 (1:1,000 in 2% ovalbumin) was added. After incubation, avidin-horseradish peroxidase (1:5,000) was added and the
colorimetric reaction was carried out using 0.4 mg/ml orthophenylene
diamine (Sigma Chemical) and 0.01%
H2O2 in substrate buffer (34.7 mM
citric acid, 66.7 mM Na2HPO4, pH 5.0).
Absorbance was read at 490 nm by microplate reader spectrophotometer
(Dynatech). The detection limit was 1.9 pg/ml mouse IL-1. Data are
expressed as picograms per milliliter of plasma.
Data analysis. Food consumption results were analyzed using a three-way ANOVA with saline vs. IL-1ra as between-group factor and saline vs. LPS and time as within-group factors. When the interaction was significant, post hoc analyses were performed using Newman-Keuls tests. Significance was set at P < 0.05. Results from RT-PCR and ELISA are expressed as means ± SE. Data were analyzed using ANOVA (ANOVA, treatment factor) followed by post hoc tests with the Newman-Keuls test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Baseline food intake did not differ between treatments (P > 0.05; Fig. 1). LPS
significantly depressed food intake for the duration of measurement
(P < 0.001). Intracerebroventricular administration of IL-1ra
significantly attenuated the depression in food intake induced by LPS
at 4, 6, 8, and 10 h after treatment (P < 0.05). Mice treated
with IL-1ra intracerebroventricularly and LPS intraperitoneally ate
significantly less than mice treated with saline
intracerebroventricularly and intraperitoneally when food intake was
measured 8 and 10 h after treatment (P < 0.05). These results
show that intracerebroventricular administration of IL-1ra attenuated
the decrease in food intake induced by LPS.
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To assess the role of IL-1 in the induction of the expression of
proinflammatory cytokines in the hypothalamus in response to LPS, mice
were pretreated intracerebroventricularly with IL-1ra or saline just
before they were injected intraperitoneally with LPS (10 µg/mouse) or saline. The effect of the different treatments under study was assessed by semiquantitative RT-PCR with 10 pg of
insert per sample. Figure 2 illustrates a
typical RT-PCR gel showing a weak basal expression of IL-1, IL-6,
and TNF- mRNAs and a marked induction of the expression of cytokine
mRNAs in the hypothalamus in response to LPS. pMus amplification was
the same in all experimental groups. After intracerebroventricular IL-1ra treatment, LPS-induced cytokine mRNA expression was attenuated (Fig. 2). In all cases, the expression of
2-microglobulin, a housekeeping gene, was not affected
by the treatments. Figure 3 illustrates in
a quantitative manner the levels of IL-1, IL-6, and TNF- mRNA
expressed as percentage of 2-microglobulin mRNA. A
one-way ANOVA revealed a significant effect of the treatments on the
expression of the different cytokines under study: IL-1 (P < 0.05), IL-6 (P < 0.01), and TNF- (P < 0.01). When administrated alone, LPS significantly induced
IL-1 (P < 0.05), IL-6 (P < 0.05), and TNF-
(P < 0.01) mRNA expression in the hypothalamus of mice compared with saline injection. IL-1ra injected
intracerebroventricularly abrogated LPS-induced IL-1, IL-6 mRNA, and
TNF- mRNA expression in the hypothalamus, as evidenced by the
comparison of the intraperitoneal LPS-intracerebroventricular saline
and intraperitoneal LPS-intracerebroventricular IL-1ra groups
[IL-1 (P < 0.05), IL-6 (P < 0.01), and
TNF- (P < 0.01)].
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To ensure that the effect of IL-1ra was specific to the brain,
IL-1 levels were measured in the plasma of IL-1ra-treated and
nontreated mice. IL-1 levels were very low in the plasma of
saline-treated mice (~8 pg/ml). LPS treatment dramatically increased
plasma levels of IL-1 (saline ip-saline icv vs. LPS ip-saline icv,
P < 0.01; saline ip-IL-1ra icv vs. LPS ip-IL-1ra icv,
P < 0.001), and this increase was not significantly altered by intracerebral administration of IL-1ra (Fig.
4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The findings of the present study show that blockade of brain IL-1 receptor activation by intracerebroventricular IL-1ra attenuates the depressing effects of systemic LPS on food intake and abrogates LPS-induced cytokine expression in the hypothalamus.
IL-1ra is a specific antagonist of IL-1 receptors that has no intrinsic
activity. It has already been shown to abrogate all known effects of
IL-1 on its target cells, and this applies to brain cells as well (2,
13). Administration of IL-1ra in the lateral ventricle of the brain
blocks the anorexic effects of IL-1 administered via the same route
(19, 27). However, when IL-1 is injected at the periphery, rather
than centrally, its depressing effects on food intake are only
partially abrogated by central IL-1ra, suggesting that the effects of
IL-1 on food intake are mediated at the periphery and in the brain
(20). The present findings that intracerebroventricular IL-1ra only partially blocked the depressing effects of intraperitoneal LPS on food
intake are in accordance with this interpretation. An alternative
hypothesis is that intracerebroventricular IL-1ra did not fully
abrogate the development of the central cytokine response to systemic
LPS by leaving intact, for example, the induction of brain interferons,
which have been shown to be involved in LPS-induced anorexia (for a
recent review see Ref. 16). This possibility clearly deserves further investigation.
The observation that systemic LPS induced the expression of brain
IL-1 at the mRNA level is in line with previous findings (11, 17,
22). In addition to inducing the expression of brain IL-1 mRNA,
systemic LPS has been shown to induce the expression of brain IL-1ra
mRNA (11). This induction is delayed compared with that of IL-1
(unpublished data), which is consistent with the concept that
endogenous IL-1ra acts as a modulator of the effects of IL-1 on its
target cells. However, changes at the mRNA level do not necessarily
recapitulate changes at the protein level. In apparent accordance with
this possible discrepancy, contradictory results concerning brain
IL-1 synthesis at the protein level have been reported. IL-1
immunoreactivity was detected in microglial cells and meningeal and
perivascular macrophages in the brain of LPS-treated rats and was
accompanied by the release of bioactive IL-1 in the extracellular
fluid (29, 32). However, no IL-1-like activity in the cerebrospinal
fluid of LPS-treated rats was detected by other authors (4, 31). The
sensitivity of the technique used for measuring IL-1 is likely to be
critical, since the levels of IL-1 that occur in the brain in
response to peripheral LPS treatment are very low.
In the present study we used semiquantitative RT-PCR to accurately
determine relative amounts of transcripts. The validity of this
technique was first checked to confirm the lack of a plateau amplification of the internal standard (pMus3) and cDNA and to ensure
that 2-microglobulin mRNA levels remained stable in
hypothalamus of mice injected systematically with LPS. Because this was
the case, the results were expressed as the ratio of cytokine
amplification to 2-microglobulin × 100. As
previously demonstrated, intraperitoneal administration of LPS induced
expression of cytokine mRNA in the hypothalamus of mice 1 h after
treatment (22). The basal expression of proinflammatory cytokines in
the hypothalamus was relatively high in the present study compared with
our observations in previous studies (22, 23). This difference could be
due to a propagation of the cytokine signal induced by implantation of
the cannula into the brain (18, 35). However, this possibility still
needs to be checked by a direct comparison of cytokine expression in the brain of implanted and nonimplanted mice. Despite this increase in
basal levels of cytokines, exogenous injection of IL-1ra in the lateral
ventricle of the brain was able to fully block the LPS-induced
expression of IL-1, TNF-, and IL-6 mRNAs. Contradictory data have
been reported concerning the effect of intracerebroventricular IL-1ra
on LPS-induced IL-6 protein (1, 24). In the rat, Luheshi et al. (24)
could not detect any effect of intracerebroventricularly injected
IL-1ra on LPS-induced IL-6 in the cerebrospinal fluid, whereas it was
blocked in the cat (1). In both studies, IL-6 was measured by ELISA.
Inasmuch as more cerebrospinal fluid can be collected from the brain of
a cat than from the brain of a rat, it might be easier to pick up
significant differences due to IL-1ra in the cat than in the rat.
In terms of mechanisms of action, IL-1ra binds to both types of IL-1 receptors: type I (IL-1RI), which is the active receptor, and type II (IL-1RII), which acts as a decoy target for IL-1 (2, 5). IL-1ra abrogates the effect of IL-1 on its receptors by preventing the formation of the complex IL-1RI-IL-1-IL-1R accessory protein, which is thought to be the transducing receptor complex (14, 34). Although these data have been obtained in peripheral immune and nonimmune cells, there is evidence that brain cells also express IL-1RI, IL-1RII, and IL-1RacP that do not differ from peripheral IL-1 receptor subtypes (10, 12, 17) and that the in vivo effects of IL-1 in the brain are mediated by IL-1RI (6, 30) and its accessory protein (unpublished observation), whereas the brain IL-1RII downregulates the effects of IL-1 (7).
The importance of hypothalamic IL-1 in the induction of proinflammatory
cytokines differs from what occurs at the periphery, where TNF- is
usually considered to play a central role in inducing the release of
IL-1 and IL-6 during bacterial infections (9). Accordingly, time-course
studies confirmed that, in response to LPS, the release of IL-1 and
IL-6 was maximal when the levels of TNF- were declining (33). The
present findings, therefore, reinforce the concept that the brain
differs from the periphery in the way the cytokine network is activated
(22).
In summary, the results obtained in the present study demonstrate that endogenous hypothalamic IL-1 plays a pivotal role in the organization of the neural components of the host response to infection.
Perspectives
Many data on the expression of proinflammatory cytokines in the brain in response to peripheral inflammatory stimuli have been collected during the last decade. However, because of the redundant properties of these cytokines, little was known about their relative importance in the organization of the brain response to systemic insults. The present findings are the first to demonstrate the key role of brain IL-1 in the organization of the hypothalamic cytokine network. These results are important, since they indicate that IL-1 is certainly a better target molecule for controlling inflammation in the brain than at the periphery.| |
ACKNOWLEDGEMENTS |
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We thank Viviane Tridon for skillful assistance with intracerebral implantation of the guide cannula in mice.
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FOOTNOTES |
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This work was supported by Institut National de la Santé et de la Recherche Médicale, Institut National de la Recherche Agronomique, Direction des Recherches Études et Techniques, and European Community BIOMED 2 Grant CT97-2492. S. Layé was supported by a Biotech training grant.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. Layé, Neuroendocrinologie Fonctionelle, Université Bordeaux 1, Ave. des Facultés, 33405 Talence, France (E-mail: s.laye{at}neurocyto.u-bordeaux.fr).
Received 20 September 1999; accepted in final form 22 December 1999.
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RESULTS
DISCUSSION
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