Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pro-inflammatory cytokines, such as tumour necrosis factor (TNF) and free radicals, such as nitric oxide (NO), are mediators of endotoxaemia. Catecholamines are in clinical use to treat the haemodynamic consequences of severe septic shock. Beta-adrenergic agonists exert many of their effects by elevation of intracellular cyclic AMP (cAMP) concentration. Cyclic AMP can modulate endotoxin-induced cytokine and NO production. Here we investigate the effect of isoproterenol pretreatment on the cytokine and NO production induced by bacterial lipopolysaccharide (LPS, 4-10 mg/kg). Pretreatment with isoproterenol (10 mg/kg) blunted the LPS-induced TNF response, increased the LPS-induced formation of interleukin-10 and interleukin-6 and reduced the LPS-induced production of NO in conscious mice. In anaesthetized rats, pretreatment with isoproterenol prevented the LPS-induced suppression of vascular contractility to norepinephrine in the thoracic aorta ex vivo. The hyporeactivity is due to expression of the inducible isoform of NO synthase (iNOS) and was restored by in vitro administration of NG-methyl-L-arginine (L-NMA), an inhibitor of NO synthase. However, L-NMA did not alter vascular contractility in control vessels or in rings taken from the LPS-treated rats pretreated with isoproterenol. Our findings suggest that, in addition to its haemodynamic actions, isoproterenol may also exert beneficial effects by modulating the endotoxin-induced inflammatory response.
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PMID:Isoproterenol regulates tumour necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxaemia. 903 18

Intracellular calcium is an important mediator of the cellular response in endotoxemia and shock. Here we investigated the effects of verapamil and diltiazem, two calcium entry blockers, on endotoxin (bacterial lipopolysaccharide, LPS)-induced production of pro- and anti-inflammatory cytokines and of nitric oxide in mice. LPS-induced interleukin-10 plasma levels were significantly enhanced, and circulating tumor necrosis factor-alpha concentrations were significantly suppressed in animals pretreated intraperitoneally with verapamil (10 mg/kg) or diltiazem (20 mg/kg). However, LPS-induced interleukin-6 levels were unaffected by the calcium antagonists. Similarly, LPS-induced production of nitrite/nitrate (breakdown products of nitric oxide) was not affected by verapamil and diltiazem. We conclude that calcium entry blockers; selectively modulate the production of some pro- and anti-inflammatory mediators in endotoxemia. These effects may contribute to the cytoprotective and anti-inflammatory effects of calcium entry blockers in shock and trauma.
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PMID:Calcium entry blockers increase interleukin-10 production in endotoxemia. 911 Apr 19

Endotoxin (lipopolysaccharide; LPS) and superantigens (exotoxins) have been identified as potent inducers of lethal shock. While endotoxin primarily interacts with CD14 receptors on macrophages, superantigens like the staphylococcal enterotoxin B (SEB) preferentially activate T cells. Both cell types are triggered to release pro-inflammatory cytokines that in turn induce lethal shock. We analyzed whether endotoxin and superantigen interact during the induction phase of lethal shock. We report that LPS and SEB operate synergistically. Lethal doses of both inducers were reduced 100-fold when given in combination. The induced serum levels of tumor necrosis factor, interleukin-6, and interferon-gamma (IFN-gamma) were elevated and remained high for a prolonged period. Moreover, synergistic action of LPS and SEB induced lethal toxic shock even without presensitization of mice with D-galactosamine (D-GalN). Opposed to D-GalN-pretreated mice, mice injected with LPS and SEB showed less liver damage, but rather apoptosis of epithelial cells in the bowel. Cyclosporin A and treatment with anti-IFN-gamma monoclonal antibody blocked the synergistic action of LPS and SEB, indicating that T cell-derived IFN-gamma is the mediator of the observed synergism. Concomitant injection of LPS and SEB had no influence on SEB-induced T cell deletion and anergy induction. Since Gram-positive and Gram-negative bacteria can be recovered from septic blood samples, the synergistic action of endotoxin and superantigens might be relevant during lethal septicemia.
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PMID:Superantigen and endotoxin synergize in the induction of lethal shock. 913 Jun 31

We have been developing both local and systemic gene therapy approaches to treat inflammatory and autoimmune diseases. To determine if systemic, constitutive expression of biologically active anti-inflammatory agents is therapeutic and/or has associated toxicity, mouse hematopoietic stem cells were infected with retroviral vectors carrying the genes for human IL-1 receptor antagonist (IL-1Ra), human soluble TNF receptor p75 (sTNFR), or the beta-galactosidase (lacZ) gene, and transplanted into lethally irradiated recipients. The serum levels of human IL-1Ra and human sTNFR in the long-term reconstituted mice, 2-7 months after transplantation, were 596 and 158 ng/ml respectively. The long-term expression of human IL-1Ra had minimal effects on the PBMC profile whereas human sTNFR expression increased the percentage of B220 and Mac.1 stained cells and decreased slightly the specific T cell subsets. The ability of these proteins to protect the transplanted mice from endotoxin treatment was determined by measuring serum interleukin-6 (IL-6) and interleukin-10 (IL-10) responses after LPS injection at 1.5, 3, 4.5 and 24 h after treatment. The IL-1Ra group showed diminished IL-10 levels and less mortality after injection of LPS. These results demonstrate that constitutive, systemic expression of IL-1Ra and sTNFR is able to confer partial protective effects following treatment with endotoxin. These results further demonstrate that gene transfer methods which result in systemic, long-term expression of immunodulatory proteins could be applied to the treatment of inflammatory diseases.
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PMID:Constitutive systemic expression of IL-1Ra or soluble TNF receptor by genetically modified hematopoietic cells suppresses LPS induction of IL-6 and IL-10. 913 39

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, acute-phase reaction, and hematopoiesis. As a first step in studying the actions of IL-6 in pigs, the regulation of IL-6 expression was examined in various swine cells, including a fibroblast cell line, peripheral blood mononuclear cells (PBMC), and alveolar macrophages. IL-6 expression in transformed swine testicular (TST) fibroblasts was enhanced by TNF and IL-1 beta and to a lesser extent by poly(I).(C) and LPS. IL-6 was induced in porcine PBMC by either LPS or PHA; however, the combination of LPS plus PHA resulted in maximal IL-6 expression. Furthermore, in PBMC cells separated by adherence, LPS was a more potent inducer than PHA in adherent cells, whereas PHA was more potent in nonadherent cells. Alveolar macrophages collected from different pigs could be divided into low and high responders with respect to IL-6 induction by LPS. IL-6 mRNA induction by LPS could be detected in only 6 of 20 donor animals. Other inflammatory cytokines (IL-8, IL-beta, and TNF) were readily induced by LPS in alveolar macrophages from both low and high responders. Treatment of low-responder alveolar macrophages with conditioned medium containing IFN-gamma did not significantly alter the capacity of these macrophages to synthesize IL-6 mRNA in response to LPS. Comparison of IL-6 production capacity by the cell types in this study revealed the following order: PBMC = high-responder alveolar macrophages >> TST.cells > low-responder alveolar macrophages. Thus, PBMC appear to be quantitatively the most significant source of IL-6 in swine on a per cell basis.
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PMID:Regulation of interleukin-6 expression in porcine immune cells. 916 22

1. The effect of dexamethasone, lipocorton-1(2-26) and an antiserum to lipocortin-1(2-26) (LCPS1) upon the hyperalgesic activities in rats of carrageenin, bradykinin, tumour necrosis factor alpha (TNF alpha), interleukin-1(2), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E beta (PGE2) and dopamine were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 micrograms), bradykinin (500 ng), TNF alpha (2.5 pg), IL-1 beta (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE2 (100 ng) and dopamine (10 micrograms), were inhibited by pretreatment with dexamethasone (0.5 mg kg-1, subcutaneously, s.c., or 0.04-5.0 micrograms/paw). 3. Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1 beta (0.5 pg) by dexamethasone (0.5 mg kg-1, s.c.) was reversed by LCPS1 (0.5 ml kg-1, injected s.c., 24 h and 1 h before hyperalgesic substances) and hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng), TNF alpha (2.5 pg) and IL-1 beta (0.5 pg), but not responses to PGE2 (100 ng), were inhibited by pretreatment with lipocortin-1(2-26) (100 micrograms/paw). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1 and dexamethasone (10 micrograms ml-1) inhibited TNF alpha release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 micrograms ml-1), and LCPS1 partially reversed the inhibition by dexamethasone. These data are consistent with an important role for endogenous lipocortin-1(2-26) in mediating the anti-hyperalgesic effect of dexamethasone, with inhibiton of TNF alpha production by lipocortin-1(2-26) contributing, in part, to this role. 4. Although arachidonic acid by itself was not hyperalgesic, the hyperalgesic response to IL-1 beta (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 micrograms) and the potentiated response was inhibited by dexamethasone (50 micrograms, i.pl.) and lipocortin-1(2-26) (100 micrograms, i.pl.). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1) inhibited/abolished PGE2 release by J774 cells stimulated with LPS (3 micrograms ml-1). These data suggest that, in inflammatory hyperalgesia, inhibition of the induction of cyclo-oxygenase 2 (COX-2), rather than phospholipase A2, by dexamethasone and lipocortin-1(2-26) accounts for the anti-hyperalgesic effects of these agents. 5. The above data support the notion that induction of lipocortin by dexamethasone plays a major role in the inhibition by dexamethasone of inflammatory hyperalgesia evoked by carrageenin, bradykinin and the cytokines TNF alpha, IL-1 beta and IL-6, and provides additional evidence that the biological activity of lipocortin resides within the peptide lipocortin-1(2-26). Further, the data suggest that inhibition of lipocortin-1(2-26) of eicosanoid production by COX-2 also contributes to the anti-hyperalgesic effect of lipocortin-1.
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PMID:Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone. 922 44

The purpose of the present study was to characterize the acute changes in the insulin-like growth factor (IGF) system in humans after administration of endotoxin (lipopolysaccharide; LPS). Escherichia coli LPS (4 ng/kg) was injected intravenously into healthy adults, and serial blood samples were collected for the next 5 h; subjects injected with saline served as time-matched controls. LPS administration resulted in a gradual decrease in the total extractable IGF-I concentration, which was reduced by approximately 20% over the final 2 h of the experiment; levels of free IGF-I were not significantly altered. LPS also produced a marked but transient elevation in growth hormone (GH) concentration. IGF-binding protein (BP)-1 levels were elevated more than fivefold 2 h after LPS injection, and thereafter levels gradually returned toward baseline. IGFBP-2 concentration also increased after LPS injection, but the maximal increase (approximately 50% above basal) was observed during the final 2 h of the protocol. In contrast, IGFBP-3 levels did not vary over the period examined in response to LPS, and there was no apparent increase in number of BP-3 proteolytic fragments. Cortisol levels were increased early and remained two- to threefold above baseline throughout the protocol. No significant alterations in serum concentration of glucose or insulin were noted. LPS also produced an early elevation in tumor necrosis factor and a later increase in interleukin-6. These data indicate that the acute changes in the GH-IGF axis in humans in response to LPS are comparable with those observed in humans in other traumatic conditions and in animal models of endotoxemia and infection.
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PMID:Acute alterations in growth hormone-insulin-like growth factor axis in humans injected with endotoxin. 924 74

Age-related changes of the immune-adrenal axis were studied in rats treated intracerebroventricularly with lipopolysaccharide (LPS, 2.5 microg/5 microl). Serum interleukin-6 (IL-6), tumor necrosis factor (TNF) and corticosterone levels were evaluated in young (3 months) and old (24 months) Sprague-Dawley rats at different time-points. Old rats showed higher IL-6 levels compared to young rats while no change was observed on TNF levels in the two age groups. Corticosterone increase induced by LPS was lower in old than in young rats. The results show that heterogeneous modifications of the immune-adrenal axis occur that could have a pathophysiological role in the altered response to brain infections during aging.
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PMID:Interleukin-6, tumor necrosis factor and corticosterone induction by central lipopolysaccharide in aged rats. 925 44

A growing body of evidence suggests that corticotrophin releasing hormone (CRH) may exert direct modulatory effects on immune cells. In the present study we assessed the effects of its precursor molecule, proCRH, on interleukin-6 (IL-6) release by human peripheral blood mononuclear cells (MNC). Human MNC were incubated with the corresponding stimuli for 24 hr. The supernatants were collected and IL-6 measured by ELISA. Conditioned medium from CHO-K1 cells stably transfected with the recombinant plasmid pEE14/rat pre-proCRH cDNA was used as the source of proCRH. Western blot analysis of this medium, using an antibody specific for the intact precursor, showed that no proCRH degradation products were present. The proCRH had an inhibitory effect on basal and LPS-stimulated release of IL-6. These results suggest that the full length CRH precursor may possess immunomodulatory properties.
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PMID:Effect of the corticotrophin releasing hormone precursor on interleukin-6 release by human mononuclear cells. 932 67

The aim of this study was to measure the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by alveolar macrophages in patients with rheumatoid arthritis and interstitial lung disease (ILD). Rheumatoid arthritis patients diagnosed by ACR criteria (n = 8) with associated ILD documented by pulmonary function tests and high resolution computerized tomography scanning, and 12 healthy volunteers (6 smokers and 6 nonsmokers). We determined the spontaneous and induced production of bacterial lipopolysaccharides (LSP), TNF-alpha and IL-6 by alveolar macrophages obtained by bronchoalveolar lavage. The macrophages were isolated by Ficoll-Hypaque gradient centrifugation and plastic adherence and cultured in serum-containing medium (low endotoxin) in the presence and absence of LPS (100 ng/ml). TNF-alpha and IL-6 levels contents were determined in supernatants by ELISA. In the patient group both spontaneous and induced production of TNF-alpha were significantly higher than in controls (p < 0.01). Macrophages stimulated with LPS in patients with rheumatoid arthritis and ILD also released greater amounts of IL-6 than did those of the healthy controls. IL-6 spontaneous and induced production was significantly lower in smokers than in nonsmokers. TNF-alpha and IL-6 production in patients with rheumatoid arthritis and ILD, studied in bronchoalveolar lavage specimens reveals that alveolar macrophages are hyperreactive in these patients, who are possibly sensitized as a consequence of the inflammatory lung process inherent to the disease. Further study is needed to define the pathogenic role of these mediators.
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PMID:[Production of tumor necrosis factor alpha and interleukin-6 by alveolar macrophages from patients with rheumatoid arthritis and interstitial pulmonary disease]. 941 Apr 34


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