Human Interleukin-1β Research Articles

Pro- and anti-inflammatory properties of human recombinant IL-1β during experimental arthritis in rats: 2. period-dependent effect

The systemic effects of human recombinant Interleukin-1β (HrIL-1β) on hindpaw edema were determined in arthitis induced by human native type II collagen (CII) with muramyl dipeptide (MDP) both injected on day 0. Daily treatment with HrIL-1β (0.2 μg sc) pretreatment, from D-1 (the day before MDP and CII were injected) to D3 significantly delayed the secondary inflammation in the uninjected left hindpaw, whereas the same treatment from D6 to D10 at the end of the “primary” inflammation, enhanced the volume of the left hindpaw. Treatment from D13 to D17 did not affect the “secondary” edema in the left hindpaw. Thus, HrIL 1β administration produces pro- or anti-inflammatory effects on a developing polyarthritis depending on when treatment is started and is most effective as an anti-inflammatory molecule when started at the peak of the the inflammatory reaction, as previously described. In view of these early findings, we have compared the effect of adding HrIL-1β along with MDP in the sensitization procedure on the time-course of CII-induced arthritis. No adjuvant effect of HrIL-1β was observed. On the contrary, HrIL-1β significantly decreased the signs of inflammation in the injected hindpaw during the secondary inflammation. In addition, the immune response to type II collagen was less in the group receiving HrIL-1β, maybe because of nonspecific increase of antigen clearance. On the other hand, the MDP sensitization procedure enhanced the incidence of CII arthritis and significantly worsened the clinical parameters in both primary and secondary inflammations.

Strong inhibition of fibrinogen binding to platelet receptor alpha IIb beta 3 by RGD sequences installed into a presentation scaffold.

In order to probe the structural constraints on binding of RGD sequences to the platelet receptor alpha IIb beta 3 we have used recombinant DNA techniques to install the RGD sequence into 'presentation scaffolds', small proteins of known 3-D structure chosen to present guest sequences in constrained orientations. Using Escherichia coli expression systems we made sequence variants in which loop residues of the immunoglobulin VL domain REI and of human interleukin-1 beta were replaced (without changing polypeptide length) by the RGD sequence at positions predicted, based on small molecule studies, to orient the RGD moiety into an active conformation. These variants do not compete for fibrinogen binding to alpha IIb beta 3 up to almost 1 mM concentration. Unfolded or proteolytically fragmented forms of these same proteins do compete, however, showing that the RGD sequences in the mutants must be prohibited from binding by constraints imposed by scaffold structure. To suppress the effects of such structural constraints we constructed two sequence variants in which RGD-containing sequences 42-57 or 44-55 from the snake venom platelet antagonist kistrin were inserted (this increasing the length of the loop) into the third complementarity determining loop of REI. Both of these variants compete strongly for fibrinogen binding with IC50s in the nM range. These results, plus data on kistrin-related peptides also presented here, suggest that the molecular scaffold REI is capable of providing to an installed sequence a structural context and conformation beneficial to binding. The results also suggest that in order to bind well to alpha IIb beta 3, RGD sequences in protein ligands must either project significantly from the surface of the scaffold and/or retain a degree of conformational flexibility within the scaffold. Molecular scaffolds like REI should prove useful in the elucidation of structure-function relationships and the discovery of new active sequences, and may also serve as the basis for novel therapeutic agents.

Influence of human recombinant interleukin-1β on the enantioselective disposition of propranolol in rats

The influence of i.v. administration of 10 mg/kg recombinant human interleukin-1β (rhIL-1/sgb), a putative mediator of inflammation, on the pharmacokinetics and metabolism of the propranolol enantiomers was studied in rats aged 3, 12 and 24 months. After oral administration of rac-propranolol to control rats of the three age groups, the plasma concentrations of ( R-propranolol) were higher than those of ( S)-propranolol. Administration of IL-1β increased the plasma concentrations of the ( R)-enantiomer markedly and significantly, those of the ( S)-enantiomer only to a lesser degree. For both enantiomers an important increase in plasma binding was found in the IL-1β-treated rats, which was linked to the increase in α 1-acid glycoprotein levels. The in vitro clearance, measured in 3-month-old rats using the 9000 g liver fraction, was for neither of the propranolol enantiomers influenced by IL-1β treatment, which is in keeping with the unchanged cytochrome P450 content. The enantioselective influence of IL-1β treatment on the pharmacokinetics of propranolol was also present in 12- and 24-month-old rats, although somewhat less pronounced in the latter group. Our results show an enantioselective influence of IL-1β treatment on the pharmacokinetics of propranolol in the rat, favouring the ( R enantiomer.

Calcium changes in rabbit CSF during endotoxin, IL-1β, and PGE 2 fever

New Zealand rabbits were chronically incannulated in the lateral ventricle and cisterna magna to assess the hypothesis that calcium concentration (Ca) of cerebrospinal fluid (CSF) varies during fevers of diverse origin. In normothermic and febrile animals recovering from surgery, CSF Ca was positively and significantly correlated to rectal temperature (TR). IV injection of E. coli endotoxin and ICV injection of human recombinant interleukin 1β (hrIL-1β) induced a TR rise of 1.7 ± 0.3°C (mean ± SEM) and 1.45 ± 0.25°C, respectively, accompanied by significant increases in CSF Ca. After endotoxin administration, maximal Ca increases ranged between 0.21 and 0.48 mM above basal values in individual animals ( p < 0.01), whereas after administration of hrIL-1β increases were 0.17 and 0.25 mM ( p < 0.05). Acetylsalicylic acid (ASA) countered the fever induced by both endotoxin and hrIL-1β administrations and concomitantly antagonized the CA increase in CSF. HrIL-1β-derived nonapeptide was characteristically devoid of pyrrogenic effect and did not modify CSF Ca. Although ICV injection of prostaglandin E 2 (PGE 2) increased TR by 2.1 ± 0.77°C, it failed to have any effect on CSF Ca. Differently from the other Ca enhancers, PGE 2, however, increased CSF protein concentration (protein). These findings suggest that brain calcium metabolism plays a role in fever development and that prostaglandin involvement is only engaged once changes in CSF calcium concentration have taken place.

Chronic intracerebral infusions of vasopressin and vasopressin antagonist modulate behavioral effects of interleukin-1 in rat

To assess the role of sex dependent brain vasopressinergic transmission in the modulation of the neural effects of interleukin-1, castrated male rats that are deficient in vasopressin were implanted intracerebroventricularly with an Accurel collodion mini device containing 10 μg AVP whereas intact male rats were implanted with a similar device containing 50 Mg of dPTyr(Me)AVP, a specific antagonist of the vasopressor—like receptors of vasopressin. Control rats in each sex group were implanted with an Accurel device containing distilled water. Acute intracerebroventricular injection of 1.25–2.50 ng recombinant human interleukin-1β decreased in a dose and time-dependent manner social investigation of a juvenile conspecific. This effect was more intense in intact rats chronically infused with dPTyr(Me)AVP and less intense in castrates infused with AVP. These results confirm the modulatory role of sex-dependent vasopressinergic neurotransmission on the neural effects of interleukin-1.

Food intake and body temperature responses of rats to recombinant human interleukin-1β and a tripeptide interleukin-1β antagonist

Food intake and body temperature are two of many factors affected by IL-1β, a cytokine which is produced in response to tissue injury and inflammatory processes. In the present experiment, a tripeptide IL-1β antagonist which blocked IL-1β-induced hyperalgesia was tested for the ability to block IL-1β-induced effects on food intake and body temperature. Food intake was decreased 4–22 h after intraperitoneal (IP) administration of 1.25, 1.88, or 2.50 μg IL-1β/rat, and 0–22 h food intake was decreased by 1.88 and 2.50 μg IL-1β/rat. The effect of 1.25 μg IL-1β/rat on food intake measured 4 and 22 h after (IP) injection was blocked by coadministration of 5 mg tripeptide IL-1β antagonist. However, 25 mg tripeptide IL-1β antagonist/rat plus 1.25 μg IL-1β/rat decreased 0–22 h food intake more than IL-1β alone. Administration (IP) of 1.25 μg IL-1β/rat increased body temperature 1°C 4 h later, and 5 and 25 mg tripeptide IL-1β antagonist/rat blocked this increase. Although food intake remained decreased after IL-1β administration alone or with 25 mg tripeptide IL-1β antagonist/rat for 22 h, body temperature returned to normal under these conditions. Thus, a tripeptide IL-1β antagonist shown to block IL-1β-induced hyperalgesia also blocked food intake and body temperature responses to IL-1β, although the effective doses of IL-1β and the tripeptide IL-1β antagonist differ by 4,000-fold when both are administered peripherally.

Dexamethasone attenuates altered insulin secretion elicited by interleukin-1β in HIT cells

The effects of dexamethasone on the modulation of insulin secretion by rccombinant human interleukin-1β (IL-1) were examined in HIT-T 15 cells. The addition of IL-1 from 1.2 × 10 −8 to 10 −10 M increased insulin secretion in the 0–4-h period after IL-1 administration and prostaglandin E 2 (PGE 2) production was suppressed by IL-1 from 1.2 × 10 8 to 10 −12 M. At all doses used, IL-1 inhibited insulin secretion in the 4–24-h period after IL-1 administration and PGE 2 levels were increased in the culture medium. In the second experiment, the addition of 10 7 M dexamethasonc prevented the inhibitory effects of IL-1 on insulin secretion. In the third experiment, dexamethasone at 10 7 M attenuated both the short-term stimulation of insulin release and the long-term suppression of insulin release caused by IL-1. It also prevented the effects of IL-1 on PGE 2 production. The present studies suggest that dexamethasone may have a suppressive action on the effects of IL-1 on in vitro insulin secretion.

Enhancement or loss of the hypophagic effect of interleukin-1 upon chronic administration

To further characterize the effect of interleukin-1 on food intake, we tested whether a tolerance to the hypophagic effect of recombinant human interleukin-1β (rhIL-1β) develops with repeated injections or continuous infusion in rats. Daily intraperitoneal (IP) injections of rhIL-1β (25,000 LAF units/kg b.wt.) for 4 days did not result in tolerance to rhIL-1β's hypophagic effect. The hypophagic effect of the same dose of rhIL-1β actually increased if injections were given every second day, when the hypophagic effect of the preceeding injection had subsided. A dose of rhIL-1β that usually did not affect food intake (5000 LAF units/kg b.wt.) reduced food intake if injected repeatedly. Continuous infusion of rhIL-1β (25,000 LAF units/kg b.wt/day) via IP-implanted osmotic minipumps caused a strong initial suppression of feeding followed by the development of tolerance to the hypophagic effect of the infused rhIL-1β. Nevertheless, hypophagia caused by a subsequent IP injection of rhIL-1β (25,000 LAF units/kg b.wt.) was enhanced. As specific antibodies to rhIL-1β could be detected in sera of only three of 11 rhIL-1β-infused rats, the observed tolerance was probably not due to a humoral immune response. The results demonstrate that, dependent on test conditions, chronic administration of rhIL-1β in the rat can lead to an enhancement or to a loss of its hypophagic effect. The reasons for this difference remain unclear.

Human Dermal Fibroblast Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-1β (IL-1β) mRNA and Protein Are Co-Stimulated by Phorbol Ester: Implication for a Homeostatic Mechanism

Although the major functions of fibroblasts are to produce extracellular matrix and to maintain a structural framework for organ systems, recent studies have demonstrated that fibroblasts are active participants in inflammatory processes by synthesizing various inflammatory mediators. In this report, we provide evidence that fibroblasts may contribute to the regulation of inflammation by the synthesis of both the intracellular form and the secretory form of interleukin-1 receptor antagonists in conjunction with interleukin-1 beta production. Indirect immunofluorescence microscopy localized interleukin-1 receptor antagonist and interleukin-1 beta proteins primarily in the fibroblast cytoplasm. Polymerase chain reaction amplification of reverse-transcribed mRNA with primers specific for the intracellular form of interleukin-1 receptor antagonist detected cDNA fragments present in both unstimulated and phorbol ester-stimulated fibroblasts, identical in molecular size to that in unstimulated keratinocytes. Amplification with primers specific for the secretory form of interleukin-1 receptor antagonist, however, detected cDNA fragments in phorbol ester-stimulated fibroblasts and phytohemagglutinin-stimulated peripheral mononuclear cells, but not in unstimulated fibroblasts or keratinocytes. The amplified fibroblast cDNA sequences for both intracellular and secretory interleukin-1 receptor antagonists were confirmed by digestion with three restriction endonucleases. By ethidium bromide visualization of amplified cDNA derived from serially diluted total cellular RNA and by Southern blot hybridization analysis of amplified cDNA, we have demonstrated that fibroblast interleukin-1 receptor antagonist mRNA and interleukin-1 beta mRNA were co-stimulated by phorbol ester. Similarly, ELISA demonstrated that fibroblast cytoplasmic interleukin-1 receptor antagonist protein and interleukin-1 beta protein were co-stimulated by phorbol ester. Our data suggests that the intracellular form of interleukin-1 receptor antagonist may be important in maintaining physiologic homeostasis in fibroblasts during interleukin-1 beta induction and release.

Effects of human recombinant IL-1β on established experimental arthritis in rats

Recent studies have reported the ambivalent properties of IL-1, in that it increases or decreases experimental arthritis depending on the dose, the mode, the site, the duration of administration, and the animal model used. In a first experiment we investigated the influence of iterative subcutaneous injections of human recombinant interleukin-1β (HrIL-1β) (0.02, 0.2 or 2 μg) on the inflammatory events in arthritic rats sensitized with type II collagen and muramyl dipeptide. The daily dose of 0.2 μg slightly reduced the pathological response score while 2 μg made it worse; the dose of 0.02 μg was always ineffective. Therefore, the long-term influence of the 0.2 μg dosage of HrIL-1β on the severity of arthritic lesions was investigated. In those experimental conditions, when compared with vehicle only, HrIL-1β slightly reduced hindpaw oedema. This effect was noticeable in severely diseased animals, but was absent in those having moderate swelling. In addition, HrIL-1β induced a delayed relapsing inflammation, whatever the severity of the arthritis. In comparison, indomethacin markedly decreased the early events of inflammation without affecting the delayed relapsing arthritic process.

Does an increase in prostaglandin E 2 in the blood circulation contribute to a febrile response in rabbits?

We investigated the effect of intravenous injection of human recombinant interleukin-1β (IL-1) on rectal temperature and prostaglandin E 2 concentration in venous and arterial blood and in the push-pull perfusate in the third ventricle of rabbits. Changes in plasma prostaglandin E 2 concentration in blood obtained from the marginal ear vein paralleled changes in body temperature during both monophasic and biphasic fevers. The plasma concentration of prostaglandin E 2 in blood obtained from the jugular vein increased during the first phase of the biphasic fever. However, no increase in the prostaglandin E 2 level in the carotid arterial blood was observed during the biphasic fever. The levels of prostaglandin E 2 in the push-pull perfusate in the third ventricle were markedly elevated during both monophasic and biphasic fevers. Intracarotid infusion of prostaglandin E 2 did not produce a fever nor result in a change in the prostaglandin E 2 concentration of the push-pull perfusate in the third ventricle. The present results suggest that prostaglandin E 2 from the blood circulation does not contribute to fever production in rabbits.

Possible involvement of interleukin-1 in ischemic brain edema formation

To determine the contribution of interleukin 1 (IL-1) on ischemic brain edema formation, the effect of recombinant human interleukin 1β (rhIL-1β), or zine protoporphyrin (ZnPP) as an IL-1 blocker, on brain edema was studied in rats. The animals were subjected to 60 min of ischemia in a middle cerebral artery occlusion model. Immediately after reperfusion, rhIL-1β at a dose of 10 ng 2 μ1 , or ZnPP at doses of 1 and 10 μ g 2 μ1 were topically applied into lateral cerebroventricle. In rhIL-1β-treated rats, ischemic brain edema formation was significantly increased in the dorsal and ventral areas of the caudate putamen 24 h after reperfusion, compared to that of vehicle-treated control rats. Furthermore, in ZnPP-treated rats, brain edema was decreased in both caudate-putamen areas. This suggests that IL-1 plays an important role in pathogenesis for post-ischemic brain edema.

On the signal transducing mechanisms involved in the synergistic interaction between interleukin-1 and bradykinin on prostaglandin biosynthesis in human gingival fibroblasts.

Recombinant human interleukin-1 beta (IL-1 beta) and bradykinin (BK) synergistically stimulate prostaglandin E2 (PGE2) formation in human gingival fibroblasts cultured for 24 h. Neither BK or IL-1 beta per se, nor their combinations, caused any acute stimulation of cellular cyclic AMP accumulation. BK, but not IL-1 beta, caused a rapid, transient rise of intracellular Ca2+ concentration ([Ca2+]i), as assessed by recordings of fura-2 fluorescence in monolayers of prelabelled gingival fibroblasts. IL-1 beta did not change the effect of BK on [Ca2+]i. Ionomycin and A23187, two calcium ionophores, synergistically potentiated the stimulatory effect of IL-1 beta on PGE2 formation. Three different phorbol esters known to activate protein kinase C also synergistically potentiated the action of IL-1 beta on PGE2 formation. Exogenously added arachidonic acid significantly enhanced the basal formation of PGE2. In IL-1 beta treated cells, the enhancement of PGE2 formation seen after addition of arachidonic acid, was synergistically upregulated by IL-1 beta. These data show that i) the synergistic interaction between IL-1 beta and BK on PGE2 formation is not due to an effect linked to an upregulation of cyclic AMP or [Ca2+]i; ii) the signal transducing mechanism by which BK interacts with IL-1 beta, however, may be linked to a BK induced stimulation of [Ca2+]i and/or protein kinase C; iii) the mechanism involved in the action of IL-1 beta may, at least partly, be due to enhancement of the biosynthesis of prostanoids mediated by an upregulation of cyclooxygenase activity.

Induction of neutral proteinase and prostanoid production in bovine nasal chondrocytes by interleukin-1 and tumor necrosis factor α: Modulation of these cellular responses by interleukin-6 and platelet-derived growth factor

We have previously reported that recombinant human interleukin-1 (IL-1) stimulates matrix erosion in bovine nasal cartilage explants (R. J. Smith et al., Inflammation 13, 367–382, 1989). This action of IL-1 is believed to be caused by matrix-degrading neutral proteinases produced by activated chondrocytes. Accordingly, we investigated the effects of recombinant human interleukin-1α (IL-1α), recombinant human interleukin-1β (IL-1β), and recombinant human tumor necrosis factor α (TNFα) on bovine nasal chondrocyte (BNC) responsiveness. IL-1α and IL-1β stimulated a time (0–72 hr) and concentration-dependent (0.01–10 ng/ml) production of collagenase, gelatinase, caseinase, and prostaglandin E 2 (PGF 2) in BNC monolayer cultures. Neutral proteinase and PGE 2 production by BNC was also induced by TNFα (0.2–200 ng/ml) in a time-dependent (0–72 hr) manner. Recombinant human interleukin-6 (IL-6) caused a concentration-dependent (6–200 ng/ml) potentiation of IL-1-stimulated neutral proteinase and PGE 2 production by BNC. However, recombinant human platelet-derived growth factor homodimer BB suppressed BNC responsiveness to IL-1. A recombinant human IL-1 receptor antagonist protein inhibited BNC activation by IL-1 but not TNFα.

Interleukin-1β depresses calcium currents in CA1 hippocampal neurons at pathophysiological concentrations

Interleukin-1 is present in the central nervous system (CNS) during acute and chronic pathological processes. In the present study, we examined the interaction between recombinant human interleukin-1β (rhIL-1β) and the voltage-dependent calcium (Ca 2+) current using the whole-cell patch clamp technique. RhIL-1β depressed the voltage-gated Ca 2+ current in acutely dissociated guinea pig hippocampal CA1 neurons. This depression is rapid and is observed at pathophysiological concentrations (⩾ 1.97 pg/10 μl)- Concomitant application of rhIL-1β and rhIL-1 receptor antagonist had no effect indicating neuroactive specificity of rhIL-1β. The depression of the inward Ca 2+ current by IL-1β may play a role in: 1. 1) the regulation of neuronal excitability; 2. 2) the induction of neurological manifestations during disease; and 3. 3) in the induction and/or progression of neurodegenerative processes.

Recombinant human interleukin‐1 β–induced increase in levels of proteoglycans, stromelysin, and leukocytes in rabbit synovial fluid

To evaluate the effects of intraarticular injection of recombinant human interleukin-1 beta (IL-1 beta) on levels of proteoglycans, stromelysin, and leukocytes in rabbit synovial fluid (SF), and to determine the effects of leukocyte depletion on SF proteoglycan and stromelysin levels. Levels of leukocytes and of proteoglycans, stromelysin, and collagenase were evaluated 12 hours after the intraarticular injection of various doses of IL-1, and over a 24-hour period after injection at a single dose level. We used a monoclonal antibody (MAb) against leukocyte integrins, which markedly depressed leukocyte accumulation in SF, to evaluate the role of synovial leukocytes on IL-1-induced increases in SF proteoglycan and stromelysin levels. Levels of both proteoglycans and stromelysin increased in the IL-1-injected joints between 4 hours and 24 hours after the injection of a single 200-ng dose of IL-1. The highest levels of stromelysin and proteoglycans were achieved with IL-1 doses greater than or equal to 100 ng. Infiltration of polymorphonuclear cells (PMN) into the joint fluid of the IL-1-injected rabbits also increased, in a dose-dependent manner. Treatment of rabbits with MAb 1B4 markedly reduced infiltration of PMN into the joint, without affecting either stromelysin or proteoglycan levels. Taken together, the data suggest that there is a coordinate increase in SF stromelysin and proteoglycan levels in rabbits injected with IL-1, and that leukocytes play a minimal role in the accumulation of proteoglycans and stromelysin in the SF.

Effects of interleukin-6 on cytochrome P450-dependent mixed-function oxidases in the rat

Intravenous treatment of male rats with recombinant human interleukin-6 (rhIL6) at 50, 100 and 200μg/kg (corresponding to 4, 8 and 16 × 10 4 U/animal, respectively) reduced the activities of hepatic microsomal cytochrome P450-dependent monoxygenases to varying degrees. Ethylmorphine- N-demethylase/ activity fell to 53% of control values, an effect similar to that induced by 2.5 μg/kg Escherichia coli lipopolysaccharide (LPS). Ethoxycoumarin- O-deethylase activity was also sensitive to inhibition, whereas IL6 had little effect on the activities of other P450-dependent enzymes, including ethoxyresorufin- O-deethylase. Pentoxyresorufin dealkylase activity, which is representative of the cytochrome P450 IIB 1 2 subfamily, was unaffected by IL6 whereas LPS reduced it to 33.7% of control values. Another hepatocyte-related parameter, serum concentration of α1-acid glycoprotein (AGP), was increased by up to 3.5-fold over baseline by IL6 and 10-fold by LPS. Recombinant human interleukin-1β (rhIL1β) 10μg/kg, corresponding to 5 × 10 4U/rat) and recombinant human tumor necrosis factor α (rhTNF) (150 μg/kg corresponding to 24 × 10 4U/rat) were both as potent as LPS (2.5 μg/kg) in increasing serum AGP levels and reducing hepatic microsomal monoxygenase activities. IL6 did not potentiate the effects of rhIL1β. Hepatic microsomal glucuronyltransferase activities were little affected by LPS and unaffected by rhIL6. Finally, rhIL6 was more potent after i.p. injection than after i.v. or s.c. injection. These results suggest that the effects of LPS, TNF and IL1 on the mixed function oxidase system in vivo may be due partly to an induction of IL6 in vivo. The different sensitivities of the enzymes to IL6 but not to IL1 or TNF may be due to the involvement of two distinct mechanisms.

Effect of recombinant human interleukin 1β (rhIL-1β) on amino acid flux in the isolated perfused rat liver

We studied the effect of recombinant human IL-1β (rhIL-1β) on hepatic amino acid (AA) flux in the isolated perfused rat liver model. Two experimental groups were used - a control group (n = 5) and a rhIL-1β-treated group (n = 5). IL-1 was added to the perfusate in two successive boluses of 0.1µg and 0.9µg, respectively 35 min (final concentration 0.67 ng/ml) and 60 min (6 ng/ml) after beginning the perfusion. In the IL-1 treated group, a reduction in flux was observed for only three AA, alanine, phenylalanine and serine. Glucose and urea production in the IL-1-treated group was slightly but not-significantly lower than in the controls.rhIL-1β thus has only minor direct effects on AA flux and gluconeogenesis in the liver and cannot therefore be held responsible for the increase in hepatic amino acid uptake during stress.

Intraperitoneal administration of recombinant human interleukin-1β inhibits osmotic thirst in the rat

Decrease in water intake after intraperitoneal injection of interleukin-1β (IL-1β) was studied in the rat. Administration of IL-1β at a dose of 20 μg/kg attenuated osmotic thirst induced by intraperitoneal injection of hypertonic saline, but did not affect hypovolemic thirst induced by subcutaneous injection of either polyethylene glycol or angiotensin II. Interleukin-1β also decreased spontaneous intake of water but not that of 1.8% saline. The results suggest that the decrease in water intake by IL-1β is caused, at least in part, by suppression of osmotic thirst but not by general suppression of behavior. The effects of IL-1β were not secondary responses accompanied by feeding behavior, since food supply was removed during the experiments. Pretreatment with indomethacin blocked the decrease in water intake by IL-1β, suggesting the involvement of production of prostaglandins.

Intracerebroventricular administration of a specific IL-1 receptor antagonist blocks food and water intake suppression induced by interleukin-1β

Intracerebroventricular (ICV) microinfusion of recombinant human interleukin-1β (rhIL-1β, 1.0 ng/rat) suppressed the short-term (2 h) food and water intakes in rats. ICV infusion of recombinant human IL-1 receptor antagonist (rhIL-1ra) had no effect on food or water intake. Concomitant ICV infusion of rhIL-1β (1.0 ng/rat) and increasing concentrations of rhIL-1ra (25 to 1000 ng/rat) resulted in a dose-dependent inhibition of the short-term food and water intake suppression induced by rhIL-1β. The highest doses of rhIL-1ra (500 and 1000 ng/rat) completely blocked the food and water intake suppression induced by rhIL-1β. This suggests specificity of IL-1β suppression of short-term feeding and drinking by a direct action in the central nervous system (CNS). This ability of rhIL-1ra may have potential therapeutic implications in acute and chronic pathological processes associated with increased levels of IL-1 and appetite suppression.