Interleukin-6 and acute ischaemic stroke.
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Acute Disease↗
Biomedical subjects
S J Hopkins
Publications and source records attributed to S J Hopkins.
A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients.
OBJECTIVES: The cytokine interleukin (IL)-1 mediates ischaemic brain damage in rodents. The endogenous, highly selective, IL-1 receptor antagonist (IL-1ra) protects against ischaemic cerebral injury in a range of experimental settings, and IL-1ra causes a marked reduction of cell death when administered peripherally or at a delay in transient cerebral ischaemia. We report here the first randomised, double blind, placebo controlled trial of recombinant human IL-1ra (rhIL-1ra) in patients with acute stroke. METHODS: Patients within 6 hours of the onset of symptoms of acute stroke were randomised to rhIL-1ra or matching placebo. Test treatment was administered intravenously by a 100 mg loading dose over 60 seconds, followed by a 2 mg/kg/h infusion over 72 h. Adverse events and serious adverse events were recorded for up to 3 months, serial blood samples were collected for biological markers up to 3 months, and 5-7 day brain infarct volume was measured by computed tomography. RESULTS: No adverse events were attributed to study treatment among 34 patients randomised. Markers of biological activity, including neutrophil and total white cell counts, C reactive protein, and IL-6 concentrations, were lower in rhIL-1ra treated patients. Among patients with cortical infarcts, clinical outcomes at 3 months in the rhIL-1ra treated group were better than in placebo treated. CONCLUSIONS: These data suggest that rhIL-1ra is safe and well tolerated in acute stroke. In addition, rhIL-1ra exhibited biological activity that is relevant to the pathophysiology and clinical outcome of ischaemic stroke. Our findings identify rhIL-1ra as a potential new therapeutic agent for acute stroke.
Acute Disease↗
Role of endogenous interleukin-1 receptor antagonist in regulating fever induced by localised inflammation in the rat.
1. Interleukin (IL)-1 is a mediator of host defence responses to inflammation and injury, including fever, but its sites of synthesis and action have not been fully elucidated. The actions of IL-1 are antagonised by IL-1 receptor antagonist (IL-1ra). The present study tested the hypothesis that IL-1 and IL-1ra are produced locally at sites of peripheral inflammation in rats, and that endogenous IL-1ra acts to limit the fever resulting from the inflammation. 2. Injection of lipopolysaccharide (LPS; 100 microg kg-1) into a subcutaneous air pouch (I.PO.) of rats induced a significant increase in body temperature. Virtually all (approximately 85 %) of the injected LPS was recovered from the pouch between 1 and 8 h (when the experiment was terminated) after injection of LPS, but LPS was undetectable (< 50 pg ml-1) in plasma at any time. Concentrations of immunoreactive IL-1alpha and IL-1beta were increased significantly in the pouch at 1, 2, 3, 5 and 8 h after injection of LPS, corresponding with the rise in body temperature and the fever peak. The appearance of IL-1ra was delayed until 2 h. Thereafter, the concentrations of IL-1beta and IL-1ra increased in parallel with the development of fever, while the concentrations of IL-1alpha remained constant. IL-1ra, but not IL-1alpha or IL-1bet, was detected in significant quantities in the plasma of LPS-injected animals. 3. Treatment of rats with an anti-IL-1ra serum (2 ml, I.PO.) at the time of injection of LPS (10 or 100 microg kg-1, I.PO.) abolished the appearance of IL-1ra in the circulation. Although neutralisation of endogenous IL-1ra did not affect the maximum body temperature reached after injection of submaximum (10 microg kg-1, I.PO.) or maximum (100 microg kg-1, I.PO.) doses of LPS, the duration of the fever was significantly prolonged, and was associated with a 3- to 4-fold increase in immunoreactive IL-1beta concentrations in the pouch fluid, but not in the plasma, at the 8 h time point. 4. These data show that effects of local (I.PO.) injection of LPS are not due to its action in the circulation or at distant sites (such as at the blood-brain barrier). These data also show that locally produced IL-1ra, in response to injection (I.PO.) of LPS, inhibits the production and/or action of locally produced IL-1beta. The ability of IL-1ra to limit the duration, rather than the magnitude of the fever, is consistent with its delayed production, relative to IL-IL-1ra, therefore, appears to play a key role in the resolution of fever induced by localised inflammatory responses.
Animals↗
Deficiency of IL-2 or IL-6 reduces lymphocyte proliferation, but only IL-6 deficiency decreases the contact hypersensitivity response.
We evaluated the importance of IL-2 and IL-6 in primary antigen-induced proliferation of lymph node cells (LNC) and the induction of contact hypersensitivity (CH). These responses were examined in cytokine-deficient mice following application of the contact sensitizer, oxazolone (OX). Proliferation and induction of IL-6 by LNC from IL-2-deficient (IL-2(-/-)) mice were reduced by approximately 95 %, relative to the proliferation of LNC from IL-2(+/+) mice, although induction and elicitation of CH responses was not significantly affected. In contrast, the proliferation of LNC from sensitized IL-6(- /-) mice was reduced by approximately 50% and the CH response was significantly reduced, relative to responses of IL-6(+/+) mice. Although nonspecific inflammatory responses induced by croton oil were similar in IL-6(+/+) and IL-6(-/-) mice, both the acute inflammatory response to OX and the second phase of the inflammatory response were significantly reduced. Thus IL-2 and IL-6 play a significant role in the total proliferative response of LNC following primary contact sensitization. However, the proliferation they promote is not critical for priming the antigen-specific effector cells responsible for eliciting CH responses and IL-6 appears to be more important for expression of the later phases of acute inflammation and the CH induced by OX.
Animals↗
Involvement of CRH in fever induced by a distinct pre-formed pyrogenic factor (PFPF).
OBJECTIVE: This study investigated the role of corticotrophin-releasing hormone (CRH) in mediating the fever induced by a novel pre-formed pyrogenic factor (PFPF), using a CRF antagonist in vivo and evaluating the capacity of PFPF to stimulate CRH release from the hypothalamus in vitro. MATERIALS AND METHODS: Male Wistar rats were used. The PFPF, induced following brief incubation of rat peritoneal macrophages with LPS and retained on 10 or 20 kDa MW cut-off membranes, was injected intracerebroventricularly. Fever was monitored using a rectal probe. Hypothalamus tissue was incubated with PFPF to establish its ability to induce CRH release. The CRH was measured by ELISA. RESULTS: PFPF induced a dose-dependent fever that was abolished by boiling or pronase treatment. Whereas both dexamethasone and indomethacin were effective in reducing interleukin- (IL) 1beta-induced fever, only dexamethasone abolished the fever induced by PFPF. The CRH antagonist, a-helical CRH9-41, abolished the fever induced by synthetic CRH, IL-8 and PFPF but not tumour necrosis factor-a (TNF-alpha). Like IL-1, PFPF was able to induce the release of CRH from rat hypothalamic tissue in vitro. CONCLUSIONS: These results suggest that the fever induced by PFPF depends on CRH release but not prostaglandin synthesis.
Animals↗
Interleukin (IL)-6 release and fever induced by a pre-formed pyrogenic factor (PFPF) derived from LPS-stimulated macrophages.
A novel pre-formed pyrogenic factor (PFPF), released by LPS-stimulated macrophages, has been identified, that induces an indomethacin-resistant fever. Its activity has to date not been found to match that of any described cytokine. In this study we observed that PFPF induced the release of large amounts of IL-6 from rat peritoneal macrophages. A combination of anti-cytokine antibodies and heat treatment excluded IL-1, tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) as being responsible for this effect. PFPF also induced interleukin (IL)-1, IL-6 and TNF-alpha in a subcutaneous air pouch, as well as increasing plasma IL-6, and induced a fever of 0.58 +/- 0.07 degrees C (3 hours) that was not reduced by indomethacin (2 mg/kg, ip). Preparative isoelectric focusing (IEF) showed that the material responsible for inducing IL-6 release had a pI between 4.7 and 5.8 and corresponded to the IEF pool that induced fever when injected intracerebroventricularly.
Animals↗
Reduction of meningeal macrophages does not decrease migration of granulocytes into the CSF and brain parenchyma in experimental pneumococcal meningitis.
Leukocyte infiltration of the CSF and brain parenchyma and other parameters of inflammation during pneumococcal meningitis were investigated after reduction of meningeal macrophages in rabbits by intracisternal injection of dichloromethylene-diphosphonate (Cl2MDP)-containing liposomes. Macrophages in the meninges were reduced, in median, by approximately 77% after three intrathecal injections of 100 microl of liposomes containing Cl2MDP at 12 h intervals. Production of the cytokines interleukin-1 and tumor necrosis factor-alpha as well as infiltration of the CSF and nervous tissue by leukocytes was not significantly altered in infected animals after treatment with Cl2MDP-containing liposomes. The median CSF concentration of neuron specific enolase (NSE) as a parameter of neuronal damage was higher in infected Cl2MDP-treated animals (median [median (25th/75th percentiles): 44.7 (33.2/54.3) microg/l vs. 13.9 (10.4/23.9) microg/l; P = 0.01]). Therefore, the reduction of meningeal macrophages does not appear to attenuate inflammation in the subarachnoid space in experimental pneumococcal meningitis. Meningeal macrophages seem, however, to be important for the protection of neuronal tissue in bacterial meningitis.
Analgesics, Non-Narcotic↗
Interferon gamma induces differential upregulation of alpha and beta chemokine secretion in colonic epithelial cell lines.
BACKGROUND: Production of chemoattractant factors by the intestinal epithelium may contribute to mucosal infiltration by inflammatory cells in inflammatory bowel disease. Secretion of the alpha chemokine interleukin 8 (IL-8), a neutrophil chemoattractant, has been widely studied, but little is known about epithelial secretion of beta chemokines, which are preferentially involved in recruiting monocytes. AIMS: To investigate the profiles of alpha and beta chemokine secretion in colonic cell lines and their differential modulation by interferon gamma (IFN-gamma), a product of activated T lymphocytes and natural killer cells. METHODS AND RESULTS: HT29-19A, a model of the CT secretory crypt cell, exhibited a parallel secretion of the alpha chemokines IL-8 and GRO alpha, which could be markedly upregulated by tumour necrosis factor alpha (TNF-alpha) and IL-1 beta. These cells showed no significant expression of the beta chemokines RANTES (regulated upon activation T cell expressed and secreted), MIP-1 alpha (macrophage inflammatory protein 1 alpha), and MCP-1 (monocyte chemotactic protein 1) under these conditions, but IFN-gamma in combination with TNF-alpha caused a dose dependent induction of RANTES and MCP-1 secretion. This was accompanied by a marked increase of RANTES mRNA. In contrast, IFN-gamma had no significant effect on TNF-alpha stimulated IL-8 secretion. Caco-2 cells, with features more typical of villus absorptive cells, were relatively poor secretors of alpha chemokines but secreted high levels of MCP-1 in response to IL-1 beta. IFN-gamma did not influence alpha or beta chemokine secretion in these cells. CONCLUSIONS: These studies suggest that intestinal epithelial cells may produce chemokines capable of attracting both neutrophils and monocytes. The ability of IFN-gamma to activate the expression of beta chemokines preferentially could facilitate the development of chronic inflammatory infiltrates.
Caco-2 Cells↗
Long-term intracerebroventricular infusion of corticotropin-releasing hormone alters neuroendocrine, neurochemical, autonomic, behavioral, and cytokine responses to a systemic inflammatory challenge.
Corticotropin-releasing hormone (CRH) was infused intracerebroventricularly into rats for 7 d via a miniosmotic pump (1 microg . microl-1 . hr-1). Body temperature and locomotor activity were recorded during the treatment using biotelemetry, whereas hippocampal serotonergic neurotransmission and free corticosterone levels were monitored using in vivo microdialysis on day 7 of CRH treatment. During the microdialysis experiment, behavioral activity was scored by assessing the time during which rats were active (locomotion, grooming, eating, drinking). Continuous intracerebroventricular infusion of CRH produced a transient increase in body temperature and locomotion. Moreover, intracerebroventricularly CRH-treated rats showed elevated free corticosterone levels with no apparent diurnal rhythm. Intraperitoneal administration of bacterial endotoxin -lipopolysaccharide (LPS); 100 microg/kg body weight- on day 7 of CRH/vehicle treatment produced a marked fever response in control animals, which was significantly blunted in intracerebroventricularly CRH-treated rats. Although free corticosterone levels reached similar peak concentrations in both intracerebroventricularly vehicle- and CRH-infused groups after LPS, this response was delayed significantly by approximately 1 hr in the intracerebroventricularly CRH-treated animals. Microdialysis experiments showed no changes in basal extracellular levels of serotonin and 5-hydroxyindoleacetic acid in intracerebroventricularly CRH-infused animals. Injection of LPS in intracerebroventricularly CRH-treated rats produced a blunted 5-HT response and a delayed onset of behavioral inhibition and other signs of sickness behavior. Assessment of the endotoxin-induced cytokine responses showed significantly enhanced plasma interleukin-1 (IL-1) and IL-6 bioactivities in the intracerebroventricularly CRH-infused animals 3 hr after injection of LPS, whereas tumor necrosis factor bioactivity responses were not different. Our data demonstrate that chronically elevated brain CRH levels produce marked changes in basal (largely CRH regulated) physiological and behavioral processes accompanied by aberrant responses to an acute challenge. The present study provides evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.
Animals↗
Fever and production of cytokines in response to repeated injections of muramyl dipeptide in guinea-pigs.
Fever and systemic plasma levels of the cytokines tumour necrosis factor alpha (TNF) and interleukin-6 (IL-6) were measured in guinea-pigs in response to single or repeated intramuscular injections of 100 micrograms/kg muramyl-dipeptide (MDP). In a pilot study (experiment 1), MDP-induced fever was monitored for 8 h. The first fever phase 90-360 min after injection of MDP was followed by the second phase which continued beyond the duration of this experiment. High circulating levels of TNF and IL-6 were detected just before body core temperature started to rise. Within the next 90 min TNF declined again by more than 90% while IL-6 remained elevated. In experiment 2, the effects of repeated injections of MDP (5 times at intervals of 3 days) on the same parameters were investigated. In this paradigm, the febrile response started earlier (60 min after injection) and the first phase of fever remained manifest until 360 min after injection, while the late phase, measured 360-720 min after injection, was attenuated. Circulating, bioactive TNF and IL-6, measured 60 and 180 min after MDP was administered, were the same in response to the first, third, and fifth injection. In experiment 3, the influence of five repeated MDP injections on the abdominal temperature was measured for 22 h, and circulating cytokines were analysed before (360 min after injection) and during (480 min after injection) the late phase of MDP-induced fever. The late phase of MDP-induced fever 7-22 h after injection was attenuated in response to the second and further administrations of this pyrogen. At 6 h after the first, third, and fifth administration of MDP, only traces of TNF alpha were measured, 2 h later no bioactive TNF was detected at all. At these times also IL-6 declined again, compared with the activity of this cytokine measured during the early phase of MDP fever, but was still present in elevated amounts. Compared with the values measured in response to the third and fifth injections of MDP, circulating IL-6 was higher 360 min and 480 min after the first injection. It remains speculative whether the longer duration of elevated IL-6 in plasma is related to the development of the long-lasting, late phase of MDP-induced fever, which was only observed after the first of five repeated injections of MDP at intervals of 3 days.
Abdomen↗
Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat.
1. The objective of the present study was to determine the sites of action of the cytokine, interleukin-1 (IL-1), in the febrile response to local inflammation in the rat, by comparing the importance of IL-1 in the local tissues, the circulation and the brain. This was achieved by injecting lipopolysaccharide (LPS, 100 micrograms kg-1) into a subcutaneous air pouch and testing the effects of blocking IL-1 action with the human recombinant interleukin-1 receptor antagonist (IL-1ra) injected either into the air pouch, intraperitoneally (1 mg kg-1, 0 + 1 h, i.p.), or intracerebroventricularly (200 micrograms/rat, 0 + 1 h, i.c.v.). 2. To investigate the effect of IL-1ra on fever and the induction of local and circulating cytokines (IL-1 and IL-6), separate experiments were performed in which groups of animals were killed 1.5, 3 or 5 h after LPS injection. Plasma and pouch fluid samples were collected for bioassay of IL-1 and IL-6. 3. Injection of LPS into the air pouch significantly increased (1.5 degrees C) body temperature, local (air pouch) concentrations of bioactive IL-1 and IL-6, and circulating bioactive IL-6, compared to saline-treated controls. 4. Injection of IL-1ra into the pouch significantly attenuated LPS fever (P < 0.001). This decrease in body temperature was associated with significant inhibition of local IL-1 bioactivity 1.5 (96%), 3 (84%) and 5 h (72%), and in bioactive IL-6 in pouch lavage fluid 1.5 (45%) and 5 h (35%), after LPS injection. The concentration of bioactive IL-6 in the plasma was significantly reduced (39%) at 3 h, when temperature was approaching the maximal value. 5. Both systemic (i.p.) and central (i.c.v.) administration of IL-1ra significantly attentuated LPS fever (P < 0.05). However, it had no effect on either local concentrations of bioactive IL-1 or IL-6, or circulating IL-6, at any of the sample points. 6. These data suggest that IL-1 is released locally, at the site of tissue inflammation and that it is an important mediator of the febrile response to local inflammation. The results also indicate that IL-1 produced locally may contribute to the production of IL-6 which is released into the circulation, and that IL-1 has important actions in the generation of fever at other sites, including the brain.
Animals↗
Health behaviors of an elderly Filipino group.
More than 69 million elderly people are expected to be living in the United States by the year 2050 (American Association of Retired Persons, 1991). For public health nurses, this rapidly growing, diverse population poses a challenge. P. Ebersol and P. Hess (1994) suggest that health care professionals must become skilled in understanding the health needs and practices of the diverse, heterogeneous aged if they are to help the elderly achieve more healthful, satisfying existences. According to two studies, M. Nemcek (1990) and J. Flaskerud and C. Rush (1989), health behaviors of the elderly vary among and within cultural groups. The purpose of this descriptive survey study was to examine how culture effects the health behaviors of 52 elderly Filipino women and men. The Health Behavior Survey was designed and used by the researchers in this study. Unhealthy behaviors identified were inclusion of fried foods in diet, weight gain, and little or no exercise. Because of the value placed on personal health by the participants, it appears the group would be receptive to a health promotion program which would increase their probability for a healthy life.
Aged↗
Local cytokine induction by LPS in the rat air pouch and its relationship to the febrile response.
Peripheral induction of cytokines is a critical event in the induction of febrile responses. The sequence of induction and site of action of these cytokines, however, remain unclear. The objective of the present study was to investigate the kinetics of local and systemic production of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), with the aim of identifying the relationship between these cytokines and the febrile response induced by injection of lipopolysaccharide (LPS) into a subcutaneous air pouch in the rat. Intrapouch injection of LPS induced dose-dependent fevers and increases in the concentration of bioactive IL-6 in the plasma. Further studies using 100 microg/kg LPS demonstrated significant increases in local (air pouch) concentrations of bioactive IL-1, TNF and IL-6, and circulating IL-6. No significant increases in TNF or IL-1 were detected in the plasma of the same animals. Local TNF was induced rapidly and peaked 1 h after LPS injection. The kinetics of local IL-1 and IL-6 induction were similar and both peaked after 3 h. The rise in local IL-6 preceded that of plasma IL-6 and reached a peak concentration that was 25-fold higher than that observed in the plasma. The data indicate that IL-1 and TNF act locally at the site of inflammation and that locally induced IL-6 is the important systemic mediator of the response.
Animals↗
Febrile response to tissue inflammation involves both peripheral and brain IL-1 and TNF-alpha in the rat.
We investigated the role and interaction between tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6 in the development of fever and their involvement in brain and systemic pathways in response to localized tissue inflammation caused by injection of turpentine (TPS) in the rat. Intramuscular injection of 10 microl TPS caused significant increases in body temperature, of up to 2 degrees C, compared with saline-treated animals. Fevers were maximal 7-8 h after injection and were preceded by significant increases in plasma bioactive IL-6. No changes in circulating bioactive IL-1 or TNF-alpha were detected. Systemic injection of IL-1 receptor antagonist (IL-1ra, 2 mg/kg i.p.) or anti-TNF-alpha antiserum (0.4 ml i.v.) almost completely abolished the febrile responses to TPS over 8 h and markedly inhibited the rise in plasma IL-6 bioactivity measured 6 h after TPS. To test the involvement of brain cytokines, anti-TNF-alpha antiserum and IL-1ra were injected intracerebroventricularly. Injections of anti-TNF-alpha antiserum (3 microl/rat i.c.v.) or IL-1ra (400 microg/kg i.c.v.) significantly (P < 0.01 and P < 0.05, respectively) inhibited fever induced by TPS. These data suggest that both localized peripheral and brain IL-1 and TNF-alpha are involved directly in the pyrogenic response to inflammation. The results indicate that, in the periphery, IL-1 and TNF-alpha cause increased production of IL-6, the most likely candidate as a circulating endogenous pyrogen.
Animals↗
Involvement of cytokines in cachexia induced by T-cell leukaemia in the rat.
The objective of this study was to investigate the involvement of cytokines (IL-1, IL-6 and TNF-alpha) in cachexia induced by T-cell leukaemia in the rat. Leukaemic rats exhibited a marked and significant increase in circulating IL-6 concentration from days 12-17 corresponding to the period of weight loss after induction of leukaemia. IL-6 plasma bioactivity correlated significantly with spleen weight and weight loss, implicating IL-6 in the cachectic response. In contrast, IL-1 and TNF-alpha plasma bioactivities were not increased compared to control rats, indicating that these cytokines are not circulating mediators of cachexia induced by T-cell leukaemia in the rat. These data suggest that IL-6 produced by the host may contribute to cachexia induced by T-cell leukaemia.
Animals↗
Antigen-induced unresponsiveness in contact sensitivity: association of depressed T lymphocyte proliferative responses with decreased interleukin 6 secretion.
Topical exposure of mice to the contact allergen oxazolone induces both 4 persistent antigen-specific down-regulation of subsequent lymph node cell (LNC) proliferative responses stimulated by the same chemical and a more transient depression of LNC proliferative responses provoked by exposure to unrelated chemical sensitizers: the latter being associated with antigenic competition in contact sensitivity. In this paper a relationship between reduced LNC proliferative activity and the secretion of interleukin 6 (IL-6) is described. Pretreatment of mice with oxazolone caused a persistent, dose-dependent inhibition of LNC proliferative activity and a parallel reduction of IL-6 secretion when mice were re-exposed, at a different site, to the same chemical. Consistent with dendritic cells (DC) being the major source of IL-6 within allergen-activated lymph nodes, depletion of Thy-lt T lymphocytes did not compromise production of this cytokine. Although in mice pretreated with oxazolone IL-6 secretion by cultured LNC was impaired markedly, the initial IL-6 content of freshly isolated LNC was apparently normal. These data suggest that the down-regulation of lymphocyte proliferative responses induced by exposure of mice to oxazolone, and the consequential impaired responsiveness, is associated with, and possibly secondary to, the reduced secretion by lymph node DC of IL-6, a cytokine that is a costimulator of T lymphocyte activation and the production of which correlates closely with the vigour of LNC proliferative activity.
Adjuvants, Immunologic↗
The role of TNF-alpha in fever: opposing actions of human and murine TNF-alpha and interactions with IL-beta in the rat.
1. The role of tumour necrosis factor-alpha (TNF-alpha) in fever is controversial. Some studies have indicated that TNF-alpha acts as a cryogen to inhibit fever, while others suggest that TNF-alpha is an endogenous pyrogen which mediates fever. The majority of studies in experimental animals supporting a cryogenic action have been conducted using human (h)TNF-alpha, which has been shown to bind only to one (p55) of the two TNF-alpha receptors in rodents. 2. The aim of the present investigation was to study the role of TNF-alpha in fever by comparing effects of hTNF-alpha, which binds only to the p55 receptor, with those of murine (m) TNF-alpha, which binds to both p55 and p75 TNF-alpha receptors, and to investigate the relationship between TNF-alpha and interleukin-1 (IL-1), an important endogenous pyrogen. 3. Injection of hTNF-alpha (0.3-10 micrograms kg-1, i.p.) had no effect on core temperature in conscious rats (measured by remote radiotelemetry), whereas mTNF-alpha (3 micrograms kg-1) induced fever which was maximal 1 h after the injection (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls). Intracerebroventricular (i.c.v.) administration of either form of TNF-alpha elicited dose-dependent fever at doses higher than 0.12 microgram kg-1. 4. Peripheral injection of hIL-1 beta (1 microgram kg-1) resulted in fever (38.3 +/- 0.2 degree C compared to 37.2 +/- 0.1 degrees C in controls at 2 h), which was significantly attenuated (P < 0.01) by co-administration of a sub-pyrogenic dose of hTNF-alpha (1 microgram kg-1), but was unaffected by co-administration of mTNF-alpha (0.1 or 0.3 microgram kg-1, i.p.). In contrast, intracerebroventricular (i.c.v.) co-administration of a sub-pyrogenic dose (0.12 microgram kg-1) of hTNF-alpha did not attenuate fever induced by intraperitoneal (i.p.) injection of IL-1 beta, and sub-pyrogenic dose (0.12 microgram kg-1, i.c.v.) of mTNF-alpha significantly prolonged the febrile response to IL-1 beta. Pretreatment of animals with anti-TNF-alpha antiserum (i.c.v.) did not affect the febrile response to systemic IL-1 beta. 5. Animals injected i.p. with a pyrogenic dose of mTNF-alpha developed fever (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls 2 h after the injection) that was completely abolished by peripheral administration of IL-1ra (2 mg kg-1, P < 0.001), while i.c.v. administration of IL-1ra (400 micrograms/rat) did not affect mTNF-alpha-induced fever. 6. These data indicate that endogenous TNF-alpha is probably a pyrogen and that previous results suggesting cryogenic actions of TNF-alpha resulted from the use of a heterologous protein in the rat. The markedly contrasting effects of mTNF-alpha and TNF-alpha could result from different interactions with the two TNF-alpha receptor subtypes. The data also suggest that fever induced by exogenous TNF-alpha is mediated via release of IL-1 beta in peripheral tissues, but not in the brain.
Animals↗
Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat.
Although a number of studies indicate that the pyrogenic activity of lipopolysaccharide (LPS) and/or interleukin (IL)-1 is mediated via induction of IL-6, this has been questioned by recent evidence demonstrating a dissociation between fever and circulating IL-6. The present study reexamines this relationship by use of human recombinant interleukin-1 receptor antagonist (IL-1ra). Injection of LPS (100 micrograms/kg ip) into rats induced fever (2.0 degrees C) that was significantly inhibited (P < 0.05) when IL-1ra (16 mg/kg ip) was given 1 and 2 h after LPS. The rise in plasma IL-6 preceded the febrile response by 1-1.5 h and, although the concentrations of bioactive IL-6 in plasma and cerebrospinal fluid (CSF) were not reduced at 4 h, at 2 h plasma and CSF IL-6 bioactivity was inhibited by 80 and 70%, respectively, after a single injection of IL-1ra (16 mg/kg ip). Intracerebroventricular injection of IL-1ra (200 micrograms/rat) inhibited LPS fever but did not affect the plasma IL-6 bioactivity measured 2 or 4 h after intraperitoneal LPS. These data show that peripheral IL-1 plays a part in the induction of both fever and the rise in plasma IL-6 that precedes it, and that IL-1 within the brain is also important in the induction of fever by LPS.
Animals↗