Injection Of IL-1beta Research Articles

PGE2 receptor subtype EP1 antagonist may inhibit central interleukin-1beta-induced fever in rats.

We have previously reported that central injection of PGE2 induces hyperthermia through its actions on EP1 receptors in rats. Because the increase in local synthesis of PGE2 is assumed to be a necessary process in a fever caused by central injection of interleukin-1beta (IL-1beta), an EP1 receptor antagonist (SC-19220) should inhibit the IL-1beta-induced fever. To test this hypothesis, we observed the effect of SC-19220 on the fever produced by injection of recombinant human IL-1beta (rhIL-1beta) into the lateral cerebroventricle (LCV) in conscious rats. Administration of SC-19220 (100 microgram) into the LCV 15 min before LCV injection of rhIL-1beta (4 ng) suppressed an initial rise in colonic temperature for 30 min, producing a fever with a longer latency to onset and a longer time to peak elevation. SC-19220, given 60 min after the central administration of rhIL-1beta, also suppressed the rhIL-1beta-induced fever 15-60 min after its injection. These findings suggest that the central IL-1beta-induced fever in rats is mediated, at least partly, by activation of EP1 receptors by PGE2.

Interleukin-1beta fever in rats: gender difference and estrous cycle influence.

Evidence exists to support the concept of sex difference in immune system activation by pyrogenic cytokines. In this study, fever development was monitored to analyze the effect of peripheral administration of interleukin (IL)-1beta (1 microgram/kg) in adult male and cycling or ovariectomized female rats with or without ovarian hormonal replacement. In male and randomly cycling female rats, a similar increase in body temperature occurred after intraperitoneal IL-1beta injection. Two representative stages of estrus with higher and lower levels of ovarian hormones (proestrus and diestrus, respectively) were chosen for study of the febrile response induced by IL-1beta. The fever induced by IL-1beta was found to be significantly higher and more prolonged in females at proestrus than at diestrus. The differential fever response seems to be mainly linked to the ovarian hormonal levels because bilaterally ovariectomized females, supplemented with sequential injections of estradiol 17beta and progesterone, showed a significantly higher IL-1beta fever than did ovariectomized rats receiving estradiol 17beta only. These results indicate that gonadal hormones can influence fever development and raise the possibility of interaction between sex hormones and thermogenesis in females during the estrous cycle.

IL-1beta increases norepinephrine level in rat frontal cortex: involvement of prostanoids, NO, and glutamate.

The effects of local administration of interleukin-1beta (IL-1beta) were studied by using an intracerebral microdialysis technique in rats. A local injection of IL-1beta (3 and 10 ng) induced an elevation of norepinephrine (NE) concentration in the medial prefrontal cortex (mPFC). IL-1-receptor antagonist (800 ng) completely blocked the IL-1beta-induced NE increase. Diclofenac, a cyclooxygenase inhibitor (500 microM), and Nomega-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor (100 microM), applied through the dialysis probe, did not affect the initial rise in NE levels observed 20 min after injection of IL-1beta but completely suppressed the late phase of IL-1beta-induced NE increase at 40 min and thereafter. In contrast, local perfusion of 6-cyno-7-nitroquinoxaline-2,3-dione, a non-N-methyl-D-aspartic acid (NMDA) glutamate-receptor antagonist (50 microM), but not DL-2-amino-5-phosphonovaleric acid, an NMDA-receptor antagonist (100 microM), blocked both phases of IL-1beta-induced NE increase. Furthermore, a microinjection of IL-1beta elevated the extracellular concentration of glutamate in the mPFC. These findings suggest that the IL-1beta-induced rise in NE levels in the mPFC is caused by activation of the glutamatergic system and the glutamate-induced increases in prostanoids and NO.

Investigation of the functional role played by the chemokine monocyte chemoattractant protein-1 in interleukin-1-induced murine peritonitis.

1. Intraperitoneal (i.p.) injection of murine recombinant IL-1beta (mrIL-1beta) produced a dose-dependent (0.5-50 ng) and time-related (0.5-2 h) secretion of murine monocyte chemoattractant protein-1 (mMCP-1; 3-4 ng per cavity) in the lavage fluids. MCP-1 mRNA could also be detected in the cell pellets by reverse transcriptase-polymerase chain reaction (RT-PCR). 2. MCP-1 levels were reduced by more than 90% by co-administration of IL-1 receptor antagonist (10 microg) (n=6, P<0.05). In contrast, an IL-1 mutant with low affinity for IL-1 receptor type I, termed yIL-1betadelta4 (50 ng), produced only a modest release of the chemokine. Treatment of mice with dexamethasone (DEX) (approximately 1 mg kg(-1) s.c.) reduced mrIL-1beta-induced mMCP-1 gene expression (apparent total inhibition) and protein release in the lavage fluids (approximately 40% reduction; n=10; P<0.05). Drastic reductions in the numbers of residential macrophages or mast cells did not modify the levels of mMCP-1 recovered in the lavage fluids. 3. Injection of mrIL-1beta produced neutrophil accumulation into the peritoneal cavities (maximal at 4 h with 1.42+/-0.15 x 10(6) cells per mouse). Co-injection of a specific polyclonal antibody against mMCP-1 reduced this process by more than 50% (n=6; P<0.05). In conclusion, we studied the mechanisms leading to the specific release of the CC chemokine mMCP-1 after in vivo administration of mrIL-1beta.

Effect of endotoxin and interleukin-1beta on corticotropin-releasing-factor and prostaglandin release by rat brainstem slices.

This study investigated the effects of lipopolysaccharide (LPS) and interleukin-1beta (IL-1beta) on corticotropin releasing factor (CRF) and prostaglandin E2 (PGE2) release by brainstem slices in vitro. First, we characterized our experimental model and demonstrated that high potassium stimulates CRF release from rat brainstem slices in a calcium dependent way. The direct stimulation of brainstem slices with IL-1beta (3-25 pM) did not modify basal or potassium-stimulated CRF release, although IL-1beta at the dose of 25 pM increased PGE2 production. Peripheral injection (i.p.) of LPS (1-10 microg/kg) or IL-1beta (1-10 microg/kg) evoked a dose-related potentiation of the ex-vivo release of CRF and PGE2 from brainstem slices. However, central (i.c.v.) administration of LPS (10-500 ng/rat) potentiated the release of CRF and PGE2 only at the dose of 500 ng/rat, whereas IL-1beta (1-100 ng/rat) failed to modify significantly the ex vivo production of both CRF and PGE2. The results of the present study provide evidence that peripheral, rather than central, endotoxin and IL-1beta administration induce the activation of brainstem CRF and PGE2, supporting the hypothesis that peripheral cytokine signalling to the CNS is mediated by stimulation of peripheral afferents.

Inducible cyclooxygenase expression in canine basilar artery after experimental subarachnoid hemorrhage.

Inducible cyclooxygenase (COX-2) has been found to play a pathological role in cerebral insult. We investigated the expression of COX-2 in the basilar artery after experimental subarachnoid hemorrhage (SAH). In a canine "two-hemorrhage" model of SAH, the basilar arteries were obtained on day 2 after a cisternal injection of autologous blood or on days 4, 6, 7, or 9 after the second injection. Basilar arteries also were obtained 12 hours after intracisternal injection a cytokine: interleukin (IL)-1 beta (0.03 microgram), IL-6 (3 micrograms), or IL-8 (10 micrograms). Western blotting with a polyclonal anti-COX-2 antibody was performed in these arteries. COX-2 protein was not demonstrated in the basilar artery in control animals without SAH. However, it was expressed in the basilar artery on days 2, 4, 6, and 7 after blood injection but not on day 9. Intracisternal injection of IL-1 beta, IL-6, or IL-8 also induced COX-2 in the basilar artery. COX-2 expression was detected in basilar arterial tissue in both acute and chronic stages after SAH. Elevation of inflammatory cytokines after SAH may be involved in the induction of COX-2, which may produce sufficient quantities of eicosanoids to affect hemodynamics after SAH.

Pain modulatory actions of cytokines and prostaglandin E2 in the brain.

Proinflammatory cytokines such as IL-1, IL-6, and TNF alpha are known to enhance nociception at peripheral inflammatory tissues. These cytokines are also produced in the brain. We found that an intracerebroventricular injection of IL-1 beta only at nonpyrogenic doses in rats reduced the paw-withdrawal latency on a hot plate and enhanced the responses of the wide dynamic range neurons in the trigeminal nucleus caudalis to noxious stimuli. This hyperalgesia, as assessed by behavioral and neuronal responses, was blocked by pretreatment with IL-1 receptor antagonist (IL-1Ra), Na salicylate, or alpha melanocyte-stimulating hormone, indicating the involvement of IL-1 receptors and the synthesis of prostanoids. IL-6 and TNF alpha at nonpyrogenic doses also induced hyperalgesia in a prostanoid-dependent way. Furthermore, the preoptic area (POA) was most sensitive to IL-1 beta (5-50 pg/kg) in the induction of behavioral hyperalgesia. The maximal response was obtained 30 min after injection of IL-1 beta at 20 pg/kg. On the other hand, an injection of IL-1 beta (20-50 pg/kg) into the ventromedial hypothalamus (VMH) prolonged the paw-withdrawal latency maximally 10 min after injection. This analgesia, as well as the intraPOA IL-1 beta-induced hyperalgesia, was completely blocked by IL-1Ra or Na salicylate. Our previous study has revealed that i.c.v. injection of PGE2 induces hyperalgesia through EP3 receptors and analgesia through EP1 receptors by its central action. The results, taken together, suggest (1) that IL-1 beta at lower doses in the brain induces hyperalgesia through EP3 receptors in the POA and (2) that the higher doses of brain IL-1 beta produces analgesia through EP1 receptors, probably, in the VMH.

Effects of interleukin-1 beta on sleep are mediated by the type I receptor.

Interleukin-1 beta (IL-1 beta) is a well characterized sleep regulatory substance. To study receptor mechanisms for the sleep-promoting effects of IL-1 beta, sleep patterns were determined in control and IL-1 type I receptor knockout (IL-1RI KO) mice with a B6x129 background after intraperitoneal injections of saline or murine recombinant IL-1 beta. The IL-1RI KO mice had slightly but significantly less sleep during the dark period compared with the controls. IL-1 beta dose dependently increased non-rapid eye movement sleep (NREMS) and suppressed rapid eye movement sleep (REMS) in the controls. The IL-1RI KO mice did not respond to IL-1 beta. In contrast, the IL-1RI KO mice increased NREMS and decreased REMS after administration of tumor necrosis factor-alpha (TNF-alpha), another well characterized sleep-promoting substance. These results 1) provide further evidence that IL-1 beta is involved in sleep regulation, 2) indicate that the effects of IL-1 beta on sleep are mediated by the type I receptor, and 3) suggest that TNF-alpha is capable of inducing sleep without the involvement of IL-1.

Central IL-1 differentially regulates peripheral IL-6 and TNF synthesis.

Centrally given interleukin (IL)-1 is known to induce a rapid rises in blood IL-6. To extend this and to examine the mechanism by which this occurs, the effects of intracerebroventricular (i.c.v.) injection of human recombinant IL-1 beta on mRNA expression of IL-6 and tumour necrosis factor (TNF) in the spleen and liver were examined in rats. I.c.v. injection of IL-1 produced a rapid rise of the tissue mRNA levels of Il-6 and TNF in both organs, prior to and/or in parallel with an increase in their serum levels. Pretreatment with chlorisondamine, a ganglionic blocking agent, inhibited the Il-6 responses, while it had little influence on the TNF responses. The results suggest that brain IL-1 induces peripheral production of IL-6, but not of TNF, through autonomic nervous system activation.

THE USE OF KNOCKOUT MICE TO UNDERSTAND THE ROLE OF CYTOKINES IN FEVER

1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques. 2. Interleukin (IL)-1beta appears to be critically involved in fever caused by some routes of infection/inflammation (e.g. localized inflammation with turpentine). This cytokine has only a small role in fevers caused by i.p. injection of lipopolysaccharide (LPS). These IL-1beta-induced fevers in knockout mice appear to be via the induction of IL-6, similar to LPS-induced fevers in rats. Interleukin-6 also appears to be critically involved in turpentine-induced fever. 3. The precise role of tumour necrosis factor (TNF) in fever is controversial. Data obtained from knockout mice lacking both TNF receptors do not support a pyrogenic role for TNF in fever either to i.p. injection of LPS, s.c. injection of turpentine or following caecal ligation and puncture. 4. The roles of these cytokines in fevers induced by injection of LPS, IL-1beta, turpentine and caecal ligation and puncture are summarized. The data show the complexity of the febrile response. Depending on the types of inflammatory/infectious stimuli, different cytokines play important roles. Because other cytokines are thought to be involved in fever (e.g. macrophage inflammatory protein, interferons), considerable work is still needed to dissect the precise roles of cytokines in fever.

Clearance of 125I-labeled interleukin-6 from brain into blood following intracerebroventricular injection in rats.

To test the hypothesis that interleukin-6 (IL-6) induced within the brain can be released into peripheral blood, 125I-labeled IL-6 was injected into the lateral cerebral ventricle of rats, and its concentration in peripheral blood followed serially. Acid-precipitable tracer appeared within 5 min of injection and entered the blood following first-order kinetics (fractional rate, 0.0116 +/- 0.0022/min). Comparison of areas under the curve of intracerebroventricular (icv) vs. iv injection showed that 37.1-46.5% of tracer injected into the lateral cerebral ventricle appeared in the blood over a 4-h period. icv IL-6 exits at least in part via venous drainage (superior sagittal sinus/aortic concentration gradient was 1.47 +/- 0.23 and 3.05 +/- 0.87 in two separate groups). Prior icv injection of human IL-1beta (100 ng) did not alter rate of degradation or of exit ofradioiodine-labeled IL-6 from the brain. These studies indicate that a relatively high proportion of IL-6 that arises in the brain enters the peripheral circulation. Direct secretion of IL-6 from brain to blood may be a mechanism by which the brain modifies peripheral metabolic, endocrine, and immune activity.

Role of interleukin-1 beta, interleukin-6, and TNF-alpha in intestinal maturation induced by dietary spermine in rats.

In the present investigation, the authors aimed to evaluate the role of cytokines in intestinal postnatal maturation induced by dietary polyamines. Neonatal rats were administered either saline (8 mumol) orally. Spermine increased interleukin-1 beta (IL-1 beta), IL-6, and TNF-alpha plasma concentration. The maximum concentrations of IL-1 beta, IL-6, and TNF-alpha were, respectively, observed at 4, 4, and 8 h posttreatment. Intraperitoneal (i.p.) injection of IL-1 beta increased the specific activity of sucrase in whole small intestine, whereas the specific activities of maltase and lactase were significantly enhanced only in the jejunum. IL-6 elicited sucrase and increased maltase specific activity in the whole small intestine, but lactase specific activity was not affected. TNF-alpha had no effect on sucrase and maltase specific activity, but a slight augmentation of lactase specific activity was detected in the jejunum. Spermine and spermidine content in the intestine was increased by i.p. injection of IL-1 beta and IL-6. Corticosterone secretion was elevated by single i.p. injection of IL-1 beta, IL-6, or TNF-alpha. These findings suggest that spermine could induce postnatal intestinal development and corticosterone secretion through a cytokine-dependent mechanism.

Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.

Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).

AV3V neurons that send axons to hypothalamic nuclei respond to the systemic injection of IL-1beta.

The single neuron activity in the anteroventral region of the third ventricle (AV3V) was extracellularly recorded in urethan and alpha-chloralose anesthetized rats. Electrical stimulation of the medial preoptic area (mPOA) and the paraventricular nucleus (PVN) revealed a reciprocal neural connection between the AV3V and these hypothalamic nuclei with an ipsilateral preponderance. All the AV3V neurons, which were antidromically activated by the stimulation of the mPOA or the PVN, altered their activity after the systemic injection of interleukin (IL)-1beta. On the other hand, only about 60% of the AV3V neurons that showed orthodromic responses were affected by IL-1beta. In seven of nine AV3V neurons that were electrophysiologically identified to send their axons to the mPOA or the PVN, the recombinant human IL-1beta-induced excitation and inhibition were attenuated by a local application of sodium salicylate through multibarreled micropipettes. These results suggest that the AV3V neurons alter their activity in response to the blood-borne IL-1beta, at least in part, through a local synthesis of prostanoids and then send the information to the mPOA and PVN.

Inhibitors of cytochrome P-450 augment fever induced by interleukin-1 beta.

Metabolites of cytochrome P-450 are produced in cells when arachidonic acid cascade is activated. Fever genesis depends largely on the cyclooxygenase branch of arachidonic acid cascade, which is caused by many stimuli, such as interleukin (IL)-1, IL-6, and interferon-alpha. To assess the significance of cytochrome P-450 branch in fever, murine recombinant IL-1 beta was bilaterally microinjected (1 ng/microliter) into the medial preoptic area and anterior hypothalamus in conscious rats treated 60 min previously with or without the cytochrome P-450 inhibitor econazole (15 mg/kg im). The IL-1 beta-induced rise in colonic temperature was enhanced after the plateau phase of fever (from 240 min after IL-1 beta) in econazole-pretreated rats (P < 0.001). Another cytochrome P-450 inhibitor, clotrimazole (15 mg/kg im), also enhanced IL-1 beta-induced fever from 160 min after IL-1 beta injection (P < 0.001). Econazole also enhanced the fever when it was given 120 min before injection of IL-1 beta (P < 0.001). The cytochrome P-450 inhibitor, however, did not affect the fever when given 10 min after IL-1 beta (P = 0.95). Econazole and clotrimazole did not alter normal body temperature (P = 0.65 and 0.73, respectively). The results suggest that the metabolite(s) of cytochrome P-450 affect the falling phase after the plateau phase of fever and act as putative endogenous antipyretic(s).

Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone.

Mice rendered deficient in IL-1 beta by gene targeting in embryonic stem cells develop and grow normally in a protected laboratory environment. Endotoxin-stimulated peritoneal macrophages from IL-1beta-deficient mice showed normal synthesis and cellular release of IL-1alpha after treatment with 5 mM ATP demonstrating that IL-1beta is not necessary for expression and release of the IL-1alpha isoform. Mice deficient in IL-1beta showed unaltered sensitivity to endotoxic shock, with or without pretreatment with D-galactosamine. In contrast, IL-1beta-deficient mice showed defective contact hypersensitivity responses to topically applied trinitrochlorobenzene (TNCB). This defect could be overcome either by application of very high doses of sensitizing antigen, or by local intradermal injection of recombinant IL-1beta immediately before antigen application. These data demonstrate an essential role for IL-1beta in contact hypersensitivity and suggest that IL-1beta acts early during the sensitization phase of response. They suggest an important role for IL-1beta in initiation of the host of response at the epidermal barrier.

Interleukin-6 (IL-6) is secreted from the brain after intracerebroventricular injection of IL-1 beta in rats.

To test the hypothesis that the brain is a source of the interleukin-6 (IL-6) that appears in the peripheral circulation of rats after intracerebroventricular (icv) injection of IL-1 beta, the concentration of bioactive IL-6 in superior sagittal sinus (SSS) blood plasma was compared with aortic plasma 4 h after icv injection of 100 ng of recombinant human IL-1 beta at a time at which cerebrospinal fluid (CSF) IL-6 concentration was found to be markedly elevated. In three separate experiments, CSF IL-6 concentration (pg/ml; values are means +/- SE) was significantly elevated after icv IL-1 beta compared with saline control injections (25,879 +/- 11,472 vs. 35.5 +/- 5; 32,323 +/- 4,945 vs. 128 +/- 29; 114,410 +/- 33,563 vs. 848 +/- 250, respectively). The concentration of plasma IL-6 (pg/ml) in the aortas of rats injected intracerebroventricularly with IL-1 was greater than in controls [252 +/- 93 vs. 36.7 +/- 8.3, P = 0.0037; 361 +/- 95 vs. 57 +/- 13, P = 0.02; 2,254 +/- 550 vs. 1,239 +/- 666, P = 0.26 (NS)]. In IL-1-injected animals, SSS venous plasma IL-6 (pg/ml) was greater than in the aorta in all three studies (1,617 +/- 357 vs. 252 +/- 93, P = 0.0011; 3,754 +/- 1,188 vs. 361 +/- 95, P = 0.024; 8,208 +/- 1,388 vs. 2,254 +/- 550, P = 0.0054). The concentration difference (pg/ml) between SSS and aorta was significantly greater after IL-1 beta injection than in diluent-injected animals (1,365 +/- 369 vs. 48.3 +/- 13, P = 0.0083; 3,393 +/- 1,203 vs. 126 +/- 59, P = 0.035; 5,954 +/- 1,260 vs. 494 +/- 774, P = 0.0042). Suppression of peripheral sympathetic activation by preganglionic cholinergic blockade (chlorisondamine, 250 micrograms sc) did not prevent the usual IL-1-induced elevation in aortic blood IL-6 (3,272 +/- 1,174 vs. 244 +/- 74 pg/ml, P = 0.0012) nor the increased SSS-aortic gradient (2,541 +/- 1,134 vs. 165 +/- 48, P = 0.0142 by Mann-Whitney comparison). Injection of rat/human corticotropin-releasing hormone (CRH; 10.0 micrograms) icv did not change IL-6 concentration in CSF or in peripheral blood. These studies demonstrated that the brain and/or its supporting structures are activated by icv IL-1 beta to release IL-6 into the blood and that the effect is not dependent on peripheral sympathetic activity or central mobilization of CRH. Direct secretion of IL-6 and possibly of other cytokines from the brain is postulated to be a pathway of neuroimmunomodulation.

Release of soluble intercellular adhesion molecule 1 into bile and serum in murine endotoxin shock

Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecules Mac-1 (CD11b/CD18) on neutrophils and its counterreceptor on endothelial cells and hepatocytes, intercellular adhesion molecule 1 (ICAM-1). To investigate a potential release of a soluble form of ICAM-1 (sICAM-1), animals received 100 micrograms/kg Salmonella abortus equi endotoxin alone or in combination with 700 mg/kg galactosamine. In endotoxin-sensitive mice (C3Heb/FeJ), injection of endotoxin did not cause liver injury but induced a time-dependent increase of sICAM-1 in serum (300%) and in bile (615%) without affecting bile flow. In galactosamine/endotoxin-treated animals, which developed liver injury, the increase in both compartments was only 97% and 104%, respectively. In either case, the increase in sICAM-1 concentrations paralleled the enhanced ICAM-1 expression in the liver. The endotoxin-resistant strain (C3H/HeJ) did not show elevated sICAM-1 levels in serum or bile after endotoxin administration. In contrast, the intravenous injection of murine tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) or IL-1 beta (13-23 micrograms/kg) into endotoxin-resistant mice induced a 225% to 364% increase in serum sICAM-1 and a 370% elevation of the biliary efflux of sICAM-1, again independent of changes in bile flow. These data indicate that cytokines are major inducers of sICAM-1 formation during endotoxemia in vivo. The described experimental model can be used to investigate the role of sICAM-1 in the pathophysiology of inflammatory liver disease. (Hepatology 1996 Mar;23(3):530-6)

Release of soluble intercellular adhesion molecule 1 into bile and serum in murine endotoxin shock

Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecules Mac-1 (CD11b/CD18) on neutrophils and its counterreceptor on endothelial cells and hepatocytes, intercellular adhesion molecule 1 (ICAM-1). To investigate a potential release of a soluble form of ICAM-1 (sICAM-1), animals received 100 micrograms/kg Salmonella abortus equi endotoxin alone or in combination with 700 mg/kg galactosamine. In endotoxin-sensitive mice (C3Heb/FeJ), injection of endotoxin did not cause liver injury but induced a time-dependent increase of sICAM-1 in serum (300%) and in bile (615%) without affecting bile flow. In galactosamine/endotoxin-treated animals, which developed liver injury, the increase in both compartments was only 97% and 104%, respectively. In either case, the increase in sICAM-1 concentrations paralleled the enhanced ICAM-1 expression in the liver. The endotoxin-resistant strain (C3H/HeJ) did not show elevated sICAM-1 levels in serum or bile after endotoxin administration. In contrast, the intravenous injection of murine tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) or IL-1 beta (13-23 micrograms/kg) into endotoxin-resistant mice induced a 225% to 364% increase in serum sICAM-1 and a 370% elevation of the biliary efflux of sICAM-1, again independent of changes in bile flow. These data indicate that cytokines are major inducers of sICAM-1 formation during endotoxemia in vivo. The described experimental model can be used to investigate the role of sICAM-1 in the pathophysiology of inflammatory liver disease.

Regulation of insulin-like growth factor (IGF)-I mRNA and peptide and IGF-binding proteins by interleukin-1.

The purpose of the present study was to determine whether interleukin (IL)-1 would alter the insulin-like growth factor (IGF) system in rats and whether this change was mediated by glucocorticoids. The IGF-I concentration was decreased in plasma (32%), liver (35%), skeletal muscle (40-50% depending on fiber type), pituitary (36%), and brain (52%), and increased in kidney (73%) 6 h after intravenous injection of IL-1 beta. IL-1 beta also decreased IGF-I mRNA levels in liver and muscle and increased expression in kidney. These changes were associated with a > 2.5-fold elevation in plasma corticosterone levels. Pretreatment of rats with the glucocorticoid receptor antagonist RU-486 prevented the IL-1 beta-induced decrease in plasma and liver IGF-I concentration and the reduction in hepatic IGF-I mRNA expression. In contrast, RU-486 did not significantly attenuate the fall in IGF-I content in skeletal muscle, heart, brain, or pituitary or the increase in IGF-I observed in kidney after IL-1 beta. Furthermore, pretreatment with RU-486 did not completely prevent the IL-1 beta-induced decrease in IGF-I mRNA in skeletal muscle. The concentration of both IGF-binding protein (BP)-1 and BP-2 was increased in plasma, liver, and muscle in response to IL-1 beta, and these changes were also not prevented by RU-486. These results indicate that the inflammatory cytokine IL-1 beta is capable of influencing multiple components of the IGF system. Whereas the enhanced endogenous production of glucocorticoids appears to mediate the IL-1 beta-induced decrease in IGF-I synthesis in liver, the changes in IGF-I content observed in other tissues and the increase in IGFBP-1 and IGFBP-2 appear to be largely glucocorticoid independent.