UNIPROT:P05231 - FACTA Search

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

We evaluated the relationship between plasma fibrinogen concentration and the serum levels of interleukin-6 (IL-6), its soluble receptor, and their complex in patients with type 2 diabetes mellitus. The study comprised 57 patients with type 2 diabetes and 15 normal healthy controls. Serum levels of IL-6, soluble IL-6 receptor (IL-6R), and circulating IL-6/IL-6R complex were determined by enzyme-linked immunosorbent assays. Correlations between the different study parameters and serum IL-6, IL-6R, or IL-6/IL-6R complex levels were determined by multiple linear regression analysis. Any association between the different study parameters and the serum levels of IL-6, IL-6R, or IL-6/IL-6R complex were determined by stepwise linear regression analysis. The serum IL-6 level in diabetic subjects was significantly higher than in normal healthy controls (3.48 +/- 3.29 pg/ml vs 0.784 +/- 0.90 pg/ml, mean +/- SD, respectively, P = 0.0001). The specific optical density of the serum IL-6/IL-6R complex in diabetic patients was also significantly higher than in normal healthy controls, although there was no significant difference in the serum IL-6R level between diabetic patients and controls. The serum IL-6 concentration was correlated significantly with the HbA(1C) level (beta = 0.58, P = 0. 04) by multiple regression analysis. Stepwise regression analysis revealed that the levels of serum IL-6 (F = 8.251), HbA(1C) (F = 1. 08), and serum urea nitrogen (F = 5.603) were associated with the plasma fibrino gen concentration. These results suggest that hyperglycaemia and increased levels of serum IL-6 can increase the plasma fibrinogen concentration, one of the known risk factors for atherosclerosis in patients with type 2 diabetes mellitus.
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PMID:Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. 1043 55

Neovascularization of the atherosclerotic plaque is responsible for its weakening and consequently for the complications of vascular disease. Macrophages are a source of growth factors that can modulate angiogenesis. In this study, we analyzed the effect of oncostatin M (OSM) on angiogenesis, as it could be involved in the development of atherosclerosis. The effect of OSM was compared with those of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). On human dermal microvasculature endothelial cells (HMEC-1s), OSM (22.5 to 112.5 pmol/L) induced a dose-dependent increase in cell proliferation greater than that induced by the classic angiogenic factors vascular endothelial growth factor (VEGF; 543 pmol/L) and basic fibroblast growth factor (bFGF; 1.1 nmol/L). LIF (19 to 475 pmol/L) induced only a 30% increase in cell proliferation, and IL-6 had no effect. Furthermore, in a modified Boyden-chamber model, OSM, LIF, and IL-6 were chemoattractant for HMEC-1s. In a tridimensional gel of fibrin, OSM increased tube formation and tube length, which were already noticeable by day 3. LIF and IL-6 induced a weaker effect that was only obvious by day 10. The angiogenic effect of OSM was also demonstrated in vivo in a rabbit corneal model: OSM was more potent than LIF, the length of the neovessels being longer with OSM than with LIF, whereas IL-6 was without effect. We tested factors that could be involved in the proliferative effect of OSM on HMEC-1s. OSM induced only a slight increase in the urokinase receptor and a 60% increase in VEGF secretion, whereas it does not modify IL-8 secretion or bFGF levels. The effect of OSM seems to depend on endothelial cell origin and cell species: OSM (up to 112.5 pmol/L) did not induce human umbilical vein endothelial cell proliferation and even had a small inhibitory effect (17%) on calf pulmonary artery endothelial cells. In conclusion, OSM induces an angiogenic effect on capillary endothelial cells, which could be, at least in part, implicated in pathological processes such as atherosclerosis or tumor growth.
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PMID:Oncostatin M induces angiogenesis in vitro and in vivo. 1044 61

Expression of the class A macrophage scavenger receptor (MSR) contributes to the uptake of modified low density lipoproteins (LDL) by macrophages and transformation of these cells into lipid-laden foam cells, which characterize atherosclerosis. Many environmental factors, in particular, proinflammatory cytokines and growth factors, can exert regulatory effects on MSR expression, whereas intracellular accumulation of cholesterol itself does not influence MSR levels to any considerable extent. In the present study, by using an in vitro model, we examined whether stimulation with interleukin-6 (IL-6), an immunoregulatory, multipotential cytokine, modulates the expression and activities of the MSR in macrophages. When treated with IL-6, macrophages derived from peripheral monocytes and phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 monocytic cells showed significantly reduced uptake and/or binding of the MSR ligand, acetylated LDL. This effect was paralleled by a reduction in the expression of MSR protein and mRNA. Analysis of MSR promoter activity in THP-1 cells transfected with an MSR promoter-reporter gene construct demonstrated decreased activity of the MSR promoter in IL-6-treated THP-1 macrophages. Electrophoretic mobility gel shift assay also showed a reduction in the binding of a transcription factor to the MSR promoter AP-1/ets elements in IL-6-treated cells. Thus, exposure to IL-6 may inhibit expression of the class A MSR in differentiated macrophages at transcriptional levels. This result suggests that this cytokine may modulate foam cell formation during atherogenesis.
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PMID:Transcriptional inhibition by interleukin-6 of the class A macrophage scavenger receptor in macrophages derived from human peripheral monocytes and the THP-1 monocytic cell line. 1044 65

Acute-phase proteins, which respond to systemic proinflammatory cytokines such as interleuken-6, are elevated in cardiovascular disease and are predictive markers of future ischemic events, even over decades. This suggests a role for proinflammatory cytokines and/or acute phase proteins in early lesion development. To explore this issue, we fed C57Bl/6 and nonobese diabetic male mice high-fat (20% total fat, 1.5% cholesterol) diets and ApoE-deficient male mice both high-fat and normal chow diets for 6 to 21 weeks, injecting them weekly with either 5000 U recombinant interleukin-6 (rIL-6) or saline buffer. Blood was collected when animals were euthanized and assayed for cytokines, acute-phase proteins, and cholesterol. Across all mice, IL-6 injection resulted in significant increases in proinflammatory cytokines (IL-6, 4.6-fold; IL-1beta, 1.6-fold; and tissue necrosis factor-alpha, 1.7-fold) and fibrinogen (1.2-fold) and with decreased concentrations of albumin (0.9-fold) in plasma. Total cholesterol levels were unchanged between rIL-6-treated and nontreated groups. Serial sections through the aortic sinus were stained with oil red O to detect fatty streaks, and area of the lesions was determined by image analysis. Although no fatty streaks were detected in the nonobese diabetic mice with or without rIL-6 treatment, rIL-6 treatment increased lesion size in C57Bl/6 and ApoE-deficient mice 1.9- to 5.1-fold over lesions in saline-treated animals. These results suggest that under the appropriate circumstances changes in circulating proinflammatory cytokines and acute-phase proteins may be more than just markers of atherosclerosis but actual participants in early lesion development.
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PMID:Interleukin-6 exacerbates early atherosclerosis in mice. 1052 65

Interleukin-6 (IL-6) is a pleiotropic cytokine, whose plasma levels are elevated in inflammatory diseases such as atherosclerosis. We have previously reported that peroxisome proliferator-activated receptor alpha (PPARalpha) ligands (fibrates) lower elevated plasma concentrations of IL-6 in patients with atherosclerosis and inhibit IL-1-stimulated IL-6 secretion by human aortic smooth muscle cells (SMC). Here, we show that aortic explants isolated from PPARalpha-null mice display an exacerbated response to inflammatory stimuli, such as lipopolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPARalpha wild-type, but not of PPARalpha-null mice, demonstrating a role for PPARalpha in this fibrate action. In human aortic SMC, fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPARalpha represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPARalpha and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPARalpha-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPARalpha, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPARalpha-mediated transcriptional repression of p65 and c-Jun. Finally, glutathione S-transferase pull-down experiments demonstrate that PPARalpha physically interacts with c-Jun, p65, and CBP. Altogether these data indicate that fibrates inhibit the vascular inflammatory response via PPARalpha by interfering with the NF-kappaB and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.
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PMID:Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. 1054 37

Oncostatin M (OSM), a cytokine first identified from activated monocytes and T lymphocytes, is one of the most potent autocrine growth factor for AIDS and Kaposi's sarcoma. Little is known about the effects of OSM on normal vascular cells. We thus exposed human aortic smooth muscle cells (hASMCs) to OSM, examined cell proliferation and morphology, and determined interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) expression. OSM had a weak antiproliferative effect. After a 4-day incubation with 100 ng/mL OSM, cell count decreased to 69+/-3% of control. However, OSM induced striking changes in hASMC morphology, characterized by a polyclonal shape, in contrast to the spindle morphological feature of control hASMCs. OSM stimulated the release of IL-6 by hASMCs in a dose-dependent way; after a 48-hour exposure, values were 8.5+/-0.7, 29.7+/-3.5, 50.9+/-4.4, and 73.8+/-7.6x10(3) U/mL (n=6) at OSM concentrations of 0, 1, 10, and 100 ng/mL, respectively. OSM induced marked expression of COX-2 protein and mRNA. Leukemia inhibitory factor had no effect on hASMCs, indicating that OSM effects on hASMCs were mediated by the OSM type II receptor and not by the leukemia inhibitory factor receptor. OSM used the JAK/STAT signaling pathway, as demonstrated by rapid phosphorylation of JAK1 and specific activation of STAT1. Interestingly, OSM acted in synergy with IL-1beta on IL-6 production and COX-2 expression. In conclusion, OSM is a novel regulator of human smooth muscle cell functions, acting in concert with IL-1beta, and OSM may play a role in major vascular diseases such as atherosclerosis.
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PMID:Oncostatin M induces interleukin-6 and cyclooxygenase-2 expression in human vascular smooth muscle cells : synergy with interleukin-1beta. 1059 Feb 38

Current knowledge indicates that high plasma levels of fibrinogen, a key protein in the hemostatic system, help predict the major ischemic complications of atherosclerosis, that is, stroke and myocardial infarction. Molecular variations at the fibrinogen genes loci have been shown to regulate fibrinogen concentrations in plasma. However, it is also known that fibrinogen is an acute phase reactant and that its plasma levels are increased by the inflammatory mediator interleukin-6 (IL-6) as a consequence of stimulated gene expression. Certain risk factors for atherosclerosis are known to cause inflammatory and proliferative events within the vessel wall, especially when combined. This raises the question of whether and to what extent high plasma fibrinogen levels in patients with major thrombotic complications of atherosclerosis could be the epiphenomena of as yet poorly elucidated issues in vascular medicine (i.e., severity of vascular damage). Screening of the fibrinogen genes loci in both young patients with established risk factors and in patients evaluated for regression of atherosclerosis who have participated in risk factor reduction programs may provide further insight into the role of genetic factors in the development of atherosclerosis and in the regulation of plasma fibrinogen levels.
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PMID:Genetic Modulation of Plasma Fibrinogen Concentrations: Possible Importance of Interleukin-6. 1060 37

Cytokine induction by dialyzer membranes has been related to several acute and chronic side effects of hemodialysis treatment, among them being immune dysfunction and progressive atherosclerosis. Surface modification of cuprophane dialyzers with the antioxidant vitamin E is a new approach to enhance biocompatibility and improve cytokine levels, as well as immune function. Twenty-one patients undergoing treatment with hemophane (HE) dialyzers were enrolled onto a crossover study with a vitamin E-coated (VE) dialyzer or a synthetic polyamide (PA) dialyzer. In vitro assays of lymphocyte activation and measurements of cytokine induction were performed to evaluate biocompatibility. Four weeks of treatment with either VE or PA dialyzers enhanced in vitro proliferation of peripheral blood leukocytes in comparison to treatment with HE membranes used before study entry. Enhancement of lymphocyte function was independent of dialysis efficiency, which was kept constant during the study. In the interdialytic interval, preactivation of monocytes for the production of interleukin-6 (IL-6) did not differ between VE or PA dialysis. In contrast, the VE membrane reduced acute production of IL-6 during a dialysis treatment, whereas the PA membrane did not. Unlike IL-6, the regulatory cytokine IL-10 is not inhibited by either membrane. This is important because IL-10 is believed to have a beneficial effect on immune function in dialysis patients. The VE membrane, despite being based on a cuprophane backbone, is similar to the highly biocompatible PA dialyzer in terms of its effect on lymphocyte function, whereas it exerts an additional suppressive effect on the overproduction of proinflammatory cytokines.
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PMID:Prospective crossover trial of the influence of vitamin E-coated dialyzer membranes on T-cell activation and cytokine induction. 1062 May 50

One of the genetic features of the Sardinian population is the high prevalence of hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers. In this population, a single mutation of beta-globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases. Because previous studies have shown that Sardinian beta-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the beta-thalassemia trait was also present in subjects with familial hypercholesterolemia (FH). In a group of 63 Sardinian patients with the clinical diagnosis of FH, we identified 21 unrelated probands carrying 7 different mutations of the LDL receptor gene, 2 already known (313+1 g>a and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R, and Fs572). The 313+1 g>a and Fs572 mutations were found in several families. In cluster Fs572, the plasma LDL cholesterol level was 5.76+/-1.08 mmol/L in subjects with beta(0)-thalassemia trait and 8.25+/-1.66 mmol/L in subjects without this trait (P<0.001). This LDL-lowering effect was confirmed in an FH heterozygote of the same cluster who had beta(0)-thalassemia major and whose LDL cholesterol level was below the 50th percentile of the distribution in the normal Sardinian population. The hypocholesterolemic effect of beta(0)-thalassemia trait emerged also when we pooled the data from all FH subjects with and without beta(0)-thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of beta(0)-thalassemia may be related to (1) the mild erythroid hyperplasia, which would increase the LDL removal by the bone marrow, and (2) the chronic activation of the monocyte-macrophage system, causing an increased secretion of some cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B-containing lipoproteins. The observation that our FH subjects with beta(0)-thalassemia trait (compared with noncarriers) have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6 (+60%) supports these hypotheses. The lifelong LDL-lowering effect of beta(0)-thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.
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PMID:Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia. 1063 24

There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions.
Atherosclerosis 2000 Feb
PMID:Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? 1065 56

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