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)

Endotoxin (lipopolysaccharide, LPS) has the property of inducing tolerance to its own biological effects. This phenomenon has been extensively studied in animal models but only few studies exist on the regulation in humans. Here we describe experiments designed to determine the cytokine regulation and cellular changes in humans during induction of LPS tolerance after repeated LPS injections. Intravenous administration of purified LPS Salmonella abortus equi to cancer patients induces high amounts of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF). Repeated injections of LPS at daily intervals resulted in a marked downregulation of the cytokine response and in the case of TNF-alpha, IL-8, G-CSF, and M-CSF the cytokine response was reduced to baseline levels. In contrast, significant increases in serum IL-6 were detected up to day 5 of repeated LPS injections. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes, followed by a marked granulocytosis. The drop in WBCs remained unaltered throughout the 5 day course of repeated LPS injections whereas the granulocyte overshoot recovery diminished gradually. When PBMCs of the cancer patients were restimulated ex vivo a marked enhancement of the capacity to produce TNF-alpha, IL-113, and IL-6 occurred, which is in contrast to the decreasing TNF-alpha serum levels obtained in vivo. In parallel, a shift in monocyte subpopulations from CD14+/CD16- to CD14+/CD16+ cells was observed. The data provide evidence that different mechanisms are implicated in the cytokine downregulation following repeated LPS injections to cancer patients. Furthermore, PBMCs from LPS tolerant patients do not demonstrate a reduction in their capacity to produce cytokines.
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PMID:Endotoxin tolerance: regulation of cytokine production and cellular changes in response to endotoxin application in cancer patients. 128 77

In vitro plasma perfusion experiments were performed using small columns containing either resin or charcoal adsorbents to assess the removal of cytokines and endotoxin. 125I-labelled tumor necrosis factor-alpha (TNF-alpha; 500 pg/ml) and interleukin-6 (IL-6; 10 ng/ml) were added individually to human plasma. Over 4 hr of perfusion, Amberlite XAD-7 resin removed 32.5% +/- 3.3% (n = 5) of the initial amount of TNF-alpha and 71.4% +/- 3.8% (n = 5) of the initial amount of IL-6. DHP-1 polyhema-coated activated charcoal removed 17.2% +/- 6.2% (n = 5) of TNF-alpha and 48.5% +/- 7.4% (n = 5) of IL-6. Preliminary experiments were performed with lipopolysaccharide (LPS; 100 ng/ml) and interleukin-1 alpha (IL-1 alpha; 500 pg/ml), which showed that, over 4 hr, Amberlite XAD-7 removed 10.3% of the initial LPS and 29.1% of IL-1 alpha, whereas DHP-1 charcoal removed 23.2% of the initial LPS and 65.3% of IL-1 alpha. In vitro plasma ultrafiltration with either polysulfone or polyacrylonitrile membranes, as used clinically in haemodialysis, was performed with recirculation of plasma containing LPS or TNF-alpha. Neither of the substances was filtered to a significant degree. In conclusion, direct removal of these inflammatory mediators from the circulation of patients with multiorgan failure due to fulminant hepatic failure or sepsis would be possible by perfusion of plasma through adsorbents but not by haemodialysis.
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PMID:In vitro plasma perfusion through adsorbents and plasma ultrafiltration to remove endotoxin and cytokines. 129 81

Glomerulonephritis (GN) results in proliferation of mesangial cells (MC), infiltration of inflammatory cells, and accumulation of extracellular matrix (ECM) proteins in the mesangium. Locally secreted cytokines may stimulate MC growth or the secretion of inflammatory mediators by MC. Interleukin-6 (IL-6) may be an autocrine cofactor in the pathogenesis of mesangioproliferative GN. We studied the regulation of IL-6 secretion by MC in response to MC-derived cytokines and ECM proteins. IL-6 secretion is stimulated in a dose-dependent manner by IL-1 alpha, TNF-alpha, and PDGF. Constitutive and LPS-induced release of IL-6 by MCs is reduced on collagen type I (coll I) compared-with uncoated surfaces. IL-6 release on collagen type IV (coll IV), however, is enhanced. In addition, MC on coll I exhibit a sixfold higher growth rate than cells on uncoated surfaces. The reduction of cytokine secretion in parallel with the stimulation of MC growth by coll I suggests that exposure to coll I may result in a change from secretory to proliferative phenotype in vitro.
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PMID:Mesangial cell-matrix interactions. Effects on mesangial cell growth and cytokine secretion. 132 20

Nitric oxide (NO), apart from its properties as a vasodilator, is a cytotoxic agent released from macrophages upon stimulation with immunomodulating agents such as interferon-gamma and endotoxin. In rat Kupffer cells endotoxin causes the release of NO as well as of tumor necrosis factor-alpha and prostaglandin E2 (PGE2). This eicosanoid and its second messenger, cyclic AMP, have been shown to increase nitric oxide formation in Kupffer cells treated with endotoxin (Gaillard et al. (1991) Pathobiology 59, 280-283). But not only added PGE2 but also the prostaglandin produced endogenously upon stimulation with endotoxin increases NO synthesis. Neither tumor necrosis factor-alpha nor interleukin-1 beta stimulate NO synthesis by themselves, but together with PGE2 they are as effective as lipopolysaccharide plus PGE2. To replace PGE2 in the combination with the cytokines, however, dibutyryl cAMP has to be present in higher concentrations than with LPS. Interleukin-6 alone or in combination with PGE2 or dibutyryl cAMP is without any effect. Anti-TNF-alpha as well as anti-PGE2 antibodies reduce the release of NO upon stimulation with LPS. Consequently, the effect of LPS on NO production seems to be in part due to the self-stimulating effect of PGE2 and some cytokines, both produced by Kupffer cells upon LPS stimulation.
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PMID:Regulation by prostaglandin E2 of cytokine-elicited nitric oxide synthesis in rat liver macrophages. 133 72

Pentoxifylline (PTX) is a methylxanthine compound known to inhibit the production of tumour necrosis factor-alpha (TNF-alpha) by monocytic cells. In this study, we found that PTX differentially regulates the production of TNF-alpha and interleukin-6 (IL-6). Indeed, PTX at high concentrations triggers the production of IL-6 but not of TNF-alpha by peripheral blood mononuclear cells (PBMC). Further experiments indicated that monocytes are responsible for this PTX-induced IL-6 production. When PBMC were stimulated with LPS, PTX was found to inhibit the secretion of TNF-alpha as well as the accumulation of TNF-alpha messenger RNA (mRNA). In contrast, no inhibitory effect was observed on the induction of IL-6. Similar results were obtained when PBMC were stimulated with OKT3 monoclonal antibody (mAb). In addition, the in vivo administration of PTX in transplant patients receiving the first dose of OKT3 allowed to decrease the systemic release of TNF-alpha but not of IL-6. Since monocytes represent a major source of TNF-alpha and IL-6 in these settings, additional experiments were performed in vitro on purified T cells stimulated with the CLB-T3/3, an anti-CD3 mAb which does not require the presence of accessory cells to activate T cells. In this system, PTX was found to inhibit the secretion of both TNF-alpha and IL-6 by T cells. We suggest that cAMP could be involved in these differential effects of PTX on production of TNF-alpha and of IL-6.
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PMID:Differential effects of pentoxifylline on the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by monocytes and T cells. 138 97

Interleukin-6 (IL-6) induces acute-phase protein synthesis in human hepatocytes. We evaluated whether the contiguous hepatic macrophages, human Kupffer cells (HKC), produce IL-6 in response to an inflammatory stimulus. HKC were harvested from collagenase-digested normal liver biopsies and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture, 5 x 10(5) HKC were repleted with fresh media with or without 2.5 micrograms/ml of endotoxin (LPS). Parallel cultures contained polymyxin-B (10 micrograms/ml) or antihuman-IL-6 antibody (4 units/ml). Timed supernatants were collected and IL-6 levels (ng/ml) measured (B9.9 proliferative bioassay). Data analysis was by the paired Student's t test. Unstimulated HKC produced negligible IL-6 levels (less than 0.150 ng/ml). Endotoxin invoked early and sustained HKC production of IL-6, which was completely (P less than 0.001) abrogated by the addition of the anti-IL-6 antibody. Polymyxin B, an LPS-inhibitor, also blocked (P less than 0.001) IL-6 production, indicating the specificity of the response to the inflammatory stimulus. This is the first evidence that HKC can produce IL-6 in response to LPS. Local intrahepatic production of IL-6 may provide a necessary paracrine signal for HKC to amplify directly neighboring hepatocyte acute-phase responses during inflammation in man.
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PMID:Endotoxin stimulates interleukin-6 production by human Kupffer cells. 142 8

A role for lipopolysaccharides (endotoxins, LPS) in 7 the pathogenesis of Reye's syndrome (RS) has previously been suggested. Impairment of hepatic LPS clearance can lead to systemic endotoxemia as previous studies by this and other laboratories have suggested for several hepatic disorders including RS. Systemic LPS may mediate many of the clinical findings associated with RS by eliciting monokines such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interleukin-8. Monoclonal antibody therapy directed at LPS, and monokines may represent a novel approach to the treatment of RS.
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PMID:Monoclonal antibody therapy in the treatment of Reye's syndrome. 147 50

Administration of diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) or endotoxin (LPS) resulted in marked alterations in hepatic drug-metabolizing enzymes in endotoxin-responsive (R) and non-endotoxin-responsive (NR) mice. A single human dose (0.5 ml) of DTP vaccine increased hexobarbital-induced sleep times to 1.6- to 1.8-fold above those of controls in both strains of mice. This effect persisted for 7 days. In contrast, Bordetella pertussis LPS-treated mice showed an increase at 1 day (3.0-fold for R mice and 1.5-fold for NR mice), which returned to control levels by day 7. Furthermore, cytochrome P-450 levels were decreased 30 to 40% 24 h after DTP vaccine administration in both R and NR mice, while after LPS administration they were decreased 30% in R mice and less than 10% in NR mice. Both spleen and liver weights of R and NR mice were increased 7 to 14 days following DTP vaccine administration. However, LPS treatment had no apparent effect on liver weights, and spleen weights of R mice were elevated from days 3 to 7. Histopathologic tissue examination showed random, multifocal inflammation with hepatocyte necrosis after DTP vaccine administration to both R and NR mice and an absence of lesions in LPS-treated mice. Premixing LPS with polymyxin eliminated the increased sleep times, but premixing DTP vaccine with polymyxin did not affect the increased sleep times. Levels of tumor necrosis factor and interleukin-6 in plasma of R mice were markedly increased after DTP and LPS treatment, while NR mice had reduced increases. These results suggest that LPS contributes to the alterations in R and NR mice seen within the first 24 h of vaccine administration but that it is not likely to contribute to the effects observed at later time points.
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PMID:Role of endotoxin in alterations of hepatic drug metabolism by diphtheria and tetanus toxoids and pertussis vaccine adsorbed. 150 Jan 88

Tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8) are inflammatory cytokines produced by alveolar macrophages (AMs) and implicated in sepsis-related adult respiratory distress syndrome (ARDS). Preliminary findings from clinical trials suggest that aerosolized delivery of the synthetic surfactant Exosurf (Burroughs Wellcome Co.) reduces mortality in patients with sepsis-induced ARDS. The purpose of the present study was to examine the effect of Exosurf on inflammatory cytokine secretion from AMs in vitro. AMs were obtained from normal nonsmoking adult volunteers. Secreted TNF, IL-1, IL-6, and IL-8 were measured by enzyme-linked immunoassays in 24 h culture fluids of AMs. Exosurf inhibited LPS-stimulated TNF, IL-1, and IL-6 secretion in a dose-dependent fashion. IL-8 secretion was not affected by Exosurf under these conditions. However, if AMs were preincubated for 24 h in media and then LPS-stimulated, IL-8 secretion was inhibited by Exosurf. Regulation of IL-8 production may differ from TNF, IL-1, and IL-6. Unstimulated cytokine secretion was not affected by any of the tested concentrations of Exosurf. The inhibitory effect of Exosurf on endotoxin-induced cytokine secretion by human AMs suggests that Exosurf may modulate inflammatory cytokine production in the lung.
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PMID:Synthetic surfactant (Exosurf) inhibits endotoxin-stimulated cytokine secretion by human alveolar macrophages. 152 Apr 90

The potential role of interleukin-6 (IL-6) was studied as an inflammatory mediator of endotoxin (or lipopolysaccharide [LPS])-induced uveitis (EIU) in the rat. In young Lewis rats, levels of intraocular IL-6, but not serum IL-6, correlated with the severity of uveitis and with aqueous humor protein levels in response to foot pad injections of LPS (P less than 0.001). Adult Lewis rats did not develop uveitis and had no intraocular IL-6, although IL-6 was released systemically. Resistance to EIU and absence of IL-6 levels in the aqueous humor, despite the ability to release serum IL-6, also were observed in brown Norway rats, irrespective of age and weight. Intravitreal injection of as little as 1 ng of human recombinant IL-6 induced uveitis in young Lewis rats. In adult Lewis rats, and in young animals made tolerant to LPS, intravitreal IL-6 still caused substantial leakage of plasma proteins into the anterior chamber but no influx of inflammatory cells. As early as 2 hr after intravitreal injection of IL-6, immunohistochemical analysis showed invasion of the iris, corneal stroma, and anterior chamber by polymorphonuclear leukocytes (PMN) and expression of major histocompatibility complex (MHC) class II antigen in the retina by large cells that were macrophage-marker ED2 negative. This was followed by massive PMN infiltration of the retinal layers and vitreous. The MHC class II antigen expression of ciliary and iris epithelium occurred at a later stage (greater than 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endotoxin-induced uveitis in the rat. The significance of intraocular interleukin-6. 154 81


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