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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The structure-function relationships of the biological activities of mutant varieties of the pleiotropic cytokine interleukin-6 (human) were measured by three assays: induction of immunoglobulin M (IgM) secretion from an Epstein-Barr virus-transformed human B cell line and induction of fibrinogen secretion from either a human hepatoma cell line or a rat hepatoma cell line. The biological effects of the cytokine were characterized by three parameters as determined by a novel analysis: effectiveness (the maximal response attainable), efficiency (the concentration yielding a half-maximal response), and complexity (a measure of heterogeneity and feedback control). Substitution of serine for cysteine was associated with a reduction in the effectiveness of interleukin-6 in both fibrinogen secretion assays. In the assay with human hepatoma cells, there was also a profound reduction in efficiency. Serine substitution in the human IgM synthesis assay appears mainly to reduce the efficiency. Deletion of amino acids 4 to 23 increased the efficiency in the rat hepatoma assay. The complexity parameter suggests the presence of multiple receptor classes or negative feedback in all three assays. Use of the proposed sequential approach to the analysis of dose-response relations in bioassays provides a more useful quantitative assessment of activities as well as more insight into the complexity of the reactions.
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PMID:Analysis of the heterogeneity of the biological responses to native and mutant human interleukin-6. 132 43

Prior studies on the in vitro hepatic acute phase response have involved either hepatoma cell lines or conventional short-term cultures of primary hepatocytes. No data are available on the response of primary hepatocytes in stable long-term culture systems. In this study, the acute phase response of rat and human hepatocytes in a new long-term culture system was examined in response to interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF-alpha). The cultured cells were sandwiched between two layers of collagen in a (double-gel) configuration which has been shown to preserve both hepatocyte function and morphology over prolonged periods of time. The stability of this culture configuration enabled us to investigate, for the first time, the temporal aspects of the response in addition to the effects of the mediators on protein secretion. Exposure of rat hepatocytes to IL-6 after culture for 16 days resulted in a 2-fold reduction of albumin secretion and a 15-fold increase in the secretion rates of fibrinogen and alpha 2-macroglobulin. In all instances, the peak response occurred at 48 h after IL-6 exposure, and all protein secretion rates returned to pretreatment values within 5 days posttreatment. Changes in the mRNA levels of these proteins in response to IL-6 corresponded with those changes seen with the secreted products, indicating pretranslational regulation. Administration of IL-1 beta to rat hepatocyte produced a similar decline of albumin secretion and a 5-fold increase of fibrinogen secretion, whereas alpha 2-macroglobulin secretion remained undisturbed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A stable long-term hepatocyte culture system for studies of physiologic processes: cytokine stimulation of the acute phase response in rat and human hepatocytes. 136 59

Okadaic acid (OA), a specific inhibitor of protein phosphatases 1 and 2A, inhibited in a dose-dependent manner (5-20 nM) the induction of C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen by interleukin-6 (IL-6) plus interleukin-1 (IL-1), and of fibrinogen by IL-6 alone, in Hep 3B cells. Induction of alpha 1-proteinase inhibitor (alpha 1-PI) by IL-6 plus IL-1 or IL-6 alone was not significantly affected by OA up to concentrations of 20 nM, above which concentration OA was toxic in Hep 3B cells. OA also inhibited the induction of CRP, fibrinogen and alpha 1-PI by IL-6 in the NPLC/PRF/5 cell line, albeit at a higher concentration (80 nM). These results suggest that the signal transduction mechanisms regulating induction of acute-phase proteins by IL-6, either alone or in combination with IL-1, are mediated by activation of protein phosphatases 1 and/or 2A.
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PMID:Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, inhibits induction of acute-phase proteins by interleukin-6 alone or in combination with interleukin-1 in human hepatoma cell lines. 137 8

We measured the levels of interleukin-6 in plasma samples from 18 consecutive burn patients, including three lethal cases, during the early postburn period. In survivors burn injury caused initial increases in interleukin-6 levels that peaked at 6 hours after burn; this was significantly higher than interleukin-6 levels in normal controls (718 +/- 216 vs 70 +/- 4 pg/ml; p < 0.01). The increment in nonsurvivors was even more prominent (11,554 +/- 4,407 pg/ml; p < 0.01). The peak interleukin-6 levels at 6 hours correlated with total burn surface area (r = 0.65, p < 0.025), and tended to be higher in patients with inhalation injury. These data provide evidence that burn injury causes rapid release of interleukin-6 according to the severity of the injury. We also measured acute-phase reactants including fibrinogen, alpha 1-antitrypsin, C1 inhibitor, and alpha 2-plasmin inhibitor. After initial declines, these four proteins increased rapidly in survivors. In addition, the peak interleukin-6 levels correlated well with the increases in fibrinogen (p < 0.025), alpha 1-antitrypsin (p < 0.01), C1 inhibitor (p < 0.01), and alpha 2-plasmin inhibitor (p < 0.0001). In contrast, despite the marked increase in interleukin-6, the levels of acute phase proteins in nonsurvivors remained low. Based on these observations, we suggest that interleukin-6 is released as an alarm signal and has a role for the wound healing in burn patients, and that the levels of interleukin-6 after injury is an indicator of the severity of burn.
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PMID:Marked increase in plasma interleukin-6 in burn patients. 143 94

Similarities between the N-terminal regions of the three subunits of the clotting protein fibrinogen--(alpha beta gamma)2--suggest that they evolved from a common progenitor. However, to date no human alpha chain has been found with the strong C-terminal homology shared by the beta and gamma chains. Here we examine the natural product of a novel fibrinogen alpha chain transcript bearing a separate open reading frame that supplies the missing C-terminal homology to the other chains. Additional splicing leads to the use of this extra sequence as a sixth exon elongating the alpha chain by 35%. Since the extended alpha chain (alpha E) is assembled into fibrinogen molecules and its synthesis is enhanced by interleukin-6, it suggests participation in both the acute phase response and normal physiology.
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PMID:Carboxy-terminal-extended variant of the human fibrinogen alpha subunit: a novel exon conferring marked homology to beta and gamma subunits. 145 96

Current knowledge indicates that high plasma levels of fibrinogen help predict stroke and myocardial infarction. It is known that plasma fibrinogen is synthesized in the liver, that interleukin-6 (IL-6) affects this synthesis, and that, when exposed to appropriate stimuli, monocytes generate a variety of monokines, including IL-6. It is also known that prolonged administration of N-3 fatty acids, ticlopidine, fibrates, pentoxifylline, or alcohol lower plasma fibrinogen levels. The mechanism(s) involved in this effect are poorly understood. However, in view of the role of IL-6 and monocytes in the regulation of plasma fibrinogen levels, it is conceivable that the lowering effect of these drugs involves effects on some steps of the regulatory machinery. In addition to fibrinogen, IL-6 regulates the synthesis of other acute-phase proteins. This raises the question of whether high plasma fibrinogen levels do reflect the response of an acute-phase reactant to the severity of the atherosclerotic vascular damage taking place. Current evidence is inconclusive with respect to this possibility. On the other hand, the epidemiological data available indicate that measurements of plasma fibrinogen should be included in the cardiovascular risk-factor profile. In view of this, we believe that information emerging from population-based studies in which plasma fibrinogen is measured is important to identify appropriate directions to be followed to address unsolved issues in the area.
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PMID:Drugs affecting plasma fibrinogen levels. 157 94

Murine hepatocytes cultured in the presence of human recombinant interleukin-6 (IL-6) show increased synthesis of fibrinogen and complement component C3 by the addition of histamine. No similar effect was achieved when murine hepatocytes were treated with histamine alone or with histamine and interleukin-1 alpha together. Using histamine-1 (H1) and H2 receptor antagonists a prevalence of histamine H1 receptor in the enhancement of IL-6-induced effect is suggested.
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PMID:Histamine modulates the interleukin-6-regulated acute phase protein synthesis in cultured murine hepatocytes. 160 40

The response of megakaryocytes and platelets to the administration of recombinant human interleukin-6 (IL-6) was investigated in normal and sublethally irradiated dogs. IL-6 was administered for 2 weeks at doses of 10 to 160 micrograms/kg/d to normal animals to assess dose-response and toxicity. Subsequently, 40, 80, or 160 micrograms/kg/d for 2 weeks was administered to animals treated with 200 cG total body irradiation. Analysis of normal dogs showed a significant increment in the platelet count detectable approximately 11 days after initiation of IL-6 at all administered doses. Large platelets greater than 6.3 microns in diameter were observed 1 day after beginning IL-6, progressively increasing to as many as 19.1% of the total circulating platelets by day 10. The ploidy distribution of the marrow megakaryocytes did not differ from the normal at doses of less than or equal to 80 micrograms/kg/d, but at 160 micrograms/kg/d, a shift toward higher ploidy cells was noted. No change in total white count was noted; however, a decrease in hematocrit was seen at all doses. In the irradiated animals, the platelet count recovered earlier in the IL-6-treated dogs than in the controls, but no consistent change in the ploidy distribution was observed irrespective of dose. Large platelets were also noted in the treated animals, comprising up to 6.9% of the total platelet count. Fibrinogen levels were elevated to greater than 4 times normal. A significant decrease in hematocrit was seen in all animals, while no consistent change was noted in the white count. Elevations in serum cholesterol, triglycerides, and alkaline phosphatase, together with a decline in serum albumin were observed in all the treated animals (both normal and irradiated), but clinical symptoms were observed only in the dogs receiving greater than or equal to 80 micrograms/kg/d. The data show that IL-6 alone is capable of enhancing platelet recovery in dogs with bone marrow suppression.
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PMID:Thrombocytopoiesis in normal and sublethally irradiated dogs: response to human interleukin-6. 162

Ethanol alters many metabolic processes within the liver. Both ethanol abuse and the inability to mount an acute phase response (APR) have been associated with an increased morbidity and mortality in critically ill patients. To determine if ethanol influences the hepatic APR, relative amounts of two different human acute phase protein mRNA's were examined in the human hepatoma cell line Hep 3B before and after exposure to ethanol. Hep 3B cells were treated with one or more of the following: ethanol ((E) 150 mM); interleukin-1 beta ((IL-1) 200 units/ml); or interleukin-6 ((IL-6) 50 units/ml). After a 12-20 hr incubation relative amounts of mRNA for a1-protease inhibitor (PI) or beta fibrinogen were determined by Northern blot hybridization. Both ethanol and IL-6 were found to induce a1-PI mRNA. Fibrinogen mRNA was induced by IL-6 but not by ethanol, and no induction of PI or fibrinogen mRNA was found with IL-1. This suggests that under certain conditions, ethanol may influence acute phase protein metabolism. To our knowledge, this is the first description of an ethanol induced alteration of acute phase protein mRNA.
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PMID:Ethanol induces a1-protease inhibitor mRNA in Hep 3B cells. 165 92

Experiments in rats suffering from primary acute adjuvant inflammation showed independent changes in serum acute phase protein concentration and macroscopic paw inflammation during antiinflammatory treatment: soybean trypsin inhibitor and horse-radish peroxidase caused antiinflammatory effects but simultaneously produced increased alpha 2 macroglobulin levels. On the other hand, cycloheximide significantly inhibited the increase of alpha 2 macroglobulin concentration in adjuvant inflammation, however, it had no antiinflammatory effect. All forms of treatment caused even some change in protein plasma levels of healthy rats which probably relates to an activation of cells producing interleukin-1, interleukin-6, and/or hepatocyte stimulating factor which trigger the synthesis of acute phase proteins in the liver. In inflamed rats, the snake venom batroxobin caused a significant decrease in the fibrinogen level whereas the paw swelling remained completely unaffected. Therefore, it seems to be doubtful whether acute phase proteins essentially contribute to the modulation of acute inflammatory reaction in primary rat adjuvant inflammation.
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PMID:Acute phase reaction in rats: independent change of acute phase protein plasma concentration and macroscopic inflammation in primary rat adjuvant inflammation. 169 77


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