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)

Polymorphisms at the beta-fibrinogen locus have been shown to be associated with plasma concentration of fibrinogen and coronary heart disease. The effect of the genetic heterogeneity of fibrinogen on carotid atherosclerosis has not been determined so far. We examined the influence of the C148 --> T polymorphism on carotid disease in a large cohort of middle-aged to elderly subjects without evidence of neuropsychiatric disease. This polymorphism is located close to the consensus sequence of the interleukin-6 element and may represent a functional sequence variant. The genotype of 399 randomly selected, neurologically asymptomatic individuals, aged 45 to 75 years, was determined by denaturing gradient gel electrophoresis. Carotid atherosclerosis was assessed by color-coded duplex scanning and was graded on a five-point scale ranging from 0 (=normal) to 5 (=complete luminal obstruction). The C/C, C/T, and T/T genotypes were noted in 226 (56.6%), 148 (37.1 %), and 25 (6.3%) individuals, respectively. The T/T genotype group demonstrated higher grades of carotid atherosclerosis than did the C/C and C/T genotypes (P=.003). Logistic regression analysis created a model of independent predictors of carotid atherosclerosis that included apolipoprotein B (odds ratio [OR], 1.17/10 mg/dL), age (OR, 2.46/10 years), lifetime tobacco consumption (OR, 1.03/1000 g), presence of the beta-fibrinogen promoter T/T genotype (OR, 6.17), plasma fibrinogen concentration (OR, 1.05/10 mg/dL), and cardiac disease (OR, 1.80). These data suggest that the beta-fibrinogen promoter T/T148 genotype represents a genetic risk factor for carotid atherosclerosis in the middle-aged to elderly.
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PMID:Beta-fibrinogen gene polymorphism (C148-->T) is associated with carotid atherosclerosis: results of the Austrian Stroke Prevention Study. 951 19

Insulin resistance is associated not only with the classic cardiovascular risk factors of hypertension and dyslipidemia, but also with several disorders of coagulation and fibrinolysis. Elevated concentrations of the fibrinolytic inhibitor plasminogen activator inhibitor-1 are associated with insulin resistance. In experimental systems, increased expression and secretion of plasminogen activator inhibitor-1 by hepatocyte and endothelial cell lines can be induced by insulin, proinsulin-like molecules, triglyceride-rich lipoproteins and oxidized LDL, as well as by inducing insulin resistance in isolated hepatocytes. Concentrations of the endothelial cell protein von Willebrand factor are elevated in insulin-resistant states, suggesting that abnormalities of capillary endothelium, as well as those reported for endothelium-dependent vasodilatation, may play a role in the etiology of insulin resistance. Levels of a third coagulation factor, fibrinogen, are elevated in insulin-resistant subjects, an association that suggests a possible role for acute-phase cytokines in the abnormalities of coagulation and endothelial function. It is proposed that the recent observations of secretion of interleukin-6 by adipose tissue, combined with the actions of adipose tissue-expressed tumor necrosis factor-alpha in obesity-induced insulin resistance, could underlie the associations of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease.
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PMID:Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent? 1018 59

C-reactive protein, a hepatic acute phase protein largely regulated by circulating levels of interleukin-6, predicts coronary heart disease incidence in healthy subjects. We have shown that subcutaneous adipose tissue secretes interleukin-6 in vivo. In this study we have sought associations of levels of C-reactive protein and interleukin-6 with measures of obesity and of chronic infection as their putative determinants. We have also related levels of C-reactive protein and interleukin-6 to markers of the insulin resistance syndrome and of endothelial dysfunction. We performed a cross-sectional study in 107 nondiabetic subjects: (1) Levels of C-reactive protein, and concentrations of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, were related to all measures of obesity, but titers of antibodies to Helicobacter pylori were only weakly and those of Chlamydia pneumoniae and cytomegalovirus were not significantly correlated with levels of these molecules. Levels of C-reactive protein were significantly related to those of interleukin-6 (r=0.37, P<0.0005) and tumor necrosis factor-alpha (r=0.46, P<0.0001). (2) Concentrations of C-reactive protein were related to insulin resistance as calculated from the homoeostasis model assessment model, blood pressure, HDL, and triglyceride, and to markers of endothelial dysfunction (plasma levels of von Willebrand factor, tissue plasminogen activator, and cellular fibronectin). A mean standard deviation score of levels of acute phase markers correlated closely with a similar score of insulin resistance syndrome variables (r=0.59, P<0.00005), this relationship being weakened only marginally by removing measures of obesity from the insulin resistance score (r=0.53, P<0.00005). These data suggest that adipose tissue is an important determinant of a low level, chronic inflammatory state as reflected by levels of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, and that infection with H pylori, C pneumoniae, and cytomegalovirus is not. Moreover, our data support the concept that such a low-level, chronic inflammatory state may induce insulin resistance and endothelial dysfunction and thus link the latter phenomena with obesity and cardiovascular disease.
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PMID:C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? 1019 25

Circulating plasminogen activator inhibitor-1 (PAI-1) levels are elevated in patients with coronary heart disease and may play an important role in atherothrombosis. Levels are also raised in obese, hypertriglyceridaemic, or insulin-resistant subjects, which predispose people to coronary heart disease. It is unclear, though, which organ is responsible for PAI-1 secretion, either in health or disease. We measured arteriovenous differences across a subcutaneous adipose tissue bed in 25 subjects without coronary heart disease, which, combined with measures of adipose tissue blood flow, provides synthetic rates. There was no net increase in levels of PAI-1 activity (median change 0.23, interquartile range -0.59, 1.21 IU x L(-1), p=0.30) or of PAI-1 antigen (mean change -0.01, SD+/-2.93 ng x mL(-1), p=0.98) in these subjects. Assuming homogeneous production of PAI-1 by all adipose tissue beds, the contribution of adipose tissue to PAI-1 activity is 3.1% (interquartile range, -11.7, +7.0%) and to PAI-1 antigen 1.6% (interquartile range -14.5, +7.3%). Arteriovenous difference of PAI-1 activity and antigen did not relate to measures of obesity, triglyceride, insulin, fatty acids, or circulating concentrations or adipose tissue production of tumour necrosis factor-alpha or interleukin-6. We conclude that, at least in healthy subjects, subcutaneous adipose tissue does not contribute significantly to circulating levels of PAI-1.
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PMID:Lack of evidence for secretion of plasminogen activator inhibitor-1 by human subcutaneous adipose tissue in vivo. 1055 79

High serum lipoprotein(a) (Lp(a)) is a risk factor for vascular disorders. Our preliminary observations suggest that, in some patients with coronary heart disease with high serum Lp(a) levels, administration of aspirin reduced Lp(a) levels. Therefore, we aimed to analyze the effects of aspirin on the production of apo(a), the expression of apolipoprotein(a) (apo(a)) mRNA and the transcriptional activity of apo(a) gene promoter. Aspirin (5 mM) reduced the apo(a) levels in culture medium of human hepatocytes and suppressed apo(a) mRNA expression to 73% and 85% of the controls, respectively. Aspirin also reduced the transcriptional activity of apo(a) gene transfected into HepG2 hepatoma cells in a dose-dependent manner, with a maximal effect at 5 mM (44.3 +/- 1.5% of the control). Sodium salicylate (5 mM) also reduced apo(a) gene transcription, whereas indomethacin (10 microM) had no effect. Deletion analysis of apo(a) gene promoter showed that promoter region extending from -30 to +138 is critical for the effect of aspirin. Furthermore, enhanced production, mRNA expression, and gene transcription of apo(a) by interleukin-6 were also inhibited by aspirin. These results demonstrate that aspirin reduces apo(a) production from hepatocytes via reduction of the transcriptional activity of apo(a) gene with suppression of apo(a) mRNA expression. The suppression of apo(a) production by aspirin may at least in part play a role in the anti-atherogenic effect of aspirin in vascular disorders.
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PMID:Aspirin reduces apolipoprotein(a) (apo(a)) production in human hepatocytes by suppression of apo(a) gene transcription. 1056 80

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.
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PMID:Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? 1065 56

The plasma levels of endothelin(ET), serum levels of tumor necrosis factor(TNF) and interleukin-6(IL-6) in 35 patients with coronary heart disease(CHD) and 20 healthy people were studied by radioimmunoassay and enzymebinded immunosorbent assay(ELISA). The results showed that the plasma ET level and the serum TNF level in the CHD group, especially the acute myocardial infarction(AMI) group, were much higher than those of the control group (P < 0.01). There was no obvious statistical difference on IL-6 levels between the narrowed coronary artery group and the control group (P > 0.05). But the serum level of IL-6 in the AMI group was significantly higher than that of the other groups (P < 0.01). These findings indicate that ET and cytokine levels may play an important role on the pathogenesis of coronary heart disease.
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PMID:[Effect on endothelin and cytokines on the pathogenesis of coronary heart disease]. 1080 72

Patients with heterozygous familial hypercholesterolemia (hFH) are at very high risk for premature coronary heart disease. In the last decade, treatment with statins has reduced cardiovascular mortality in these patients. The aim of this study was to analyze arterial endothelial function assessed as flow-mediated dilatation (FMD) and soluble E-selectin (sE-selectin) levels in patients with hFH under a long-term lipid-lowering treatment. Twenty-five patients who completed the study received a dose of simvastatin to achieve a treatment goal of at least 30% reduction in serum low-density lipoprotein (LDL)-cholesterol (LDL-C) for 52 weeks. Functional and biochemical measurements were taken at entry, and at week 12 and 52 of treatment. FMD was measured by vascular ultrasound of the brachial artery. sE-selectin, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 were determined by enzyme linked immunosorbent assay (ELISA). LDL-C levels were significantly reduced by treatment at week 12 and maintained at week 52 (reduction vs. baseline, 44+/-12 and 43+/-11%, respectively, P<0.0001). A significant improvement in endothelial function, measured as FMD (baseline, 4.7+/-6.2%; 12 weeks, 12.3+/-5.9%; 52 weeks, 9.7+/-4.7%; P<0.005) and a reduction in sE-selectin levels (baseline, 16.2+/-3.4 ng/ml; 12 weeks, 11.0+/-3.2 ng/ml; 52 weeks, 12.3+/-4.2 ng/ml; P<0.01) were observed. Endothelial-independent relaxation induced by nitroglycerin was not modified during the study. Our results indicate that a long-term treatment with simvastatin produced a sustained beneficial effect in endothelial function in hFH patients.
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PMID:Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin. 1147 43

Various hormones can influence the expression of interleukin-6 (IL-6) and oestrogens are the most extensively studied. There is, however, controversy about the nature of the IL-6 secreted by human cells and its regulation by 17beta-oestradiol. The aim of this work was to clarify whether oestrogen deprivation after menopause may contribute to an enhanced IL-6 production by peripheral blood mononuclear cells (PBMC) in postmenopausal women. Twenty-two healthy postmenopausal women, age range 45-63 years, with clinical symptoms of oestrogen deficiency were enrolled in the study. The control group consisted of 16 healthy young women, age range 22-31 years, with regular menses and who were not taking oral contraceptives. Levels of IL-6 in the sera and PBMC culture supernatants were measured by the biological B9 cell-proliferation assay and expression of the IL-6 gene in non-stimulated PBMC was detected by RT-PCR. The effect of 17beta-oestradiol on spontaneous IL-6 production by the PBMC of postmenopausal women was also studied in vitro and in vivo. Seventeen out of the twenty-two postmenopausal women were given hormonal replacement therapy of 50 microg 17beta-oestradiol/day transdermally and the spontaneous production of IL-6 by the PBMC was analysed after 6 and 12 months of treatment. The postmenopausal women had significantly higher serum levels of IL-6 than the young controls. The spontaneous production of IL-6 by non-stimulated PBMC into the culture supernatants was also significantly higher in the postmenopausal women compared with the young. We also found that IL-6 gene expression was present in the non-stimulated PBMC isolated directly from the venous blood of the majority of the postmenopausal women. Women with IL-6 gene expression in the non-stimulated PBMC had significantly lower serum levels of 17beta-oestradiol compared with those where the IL-6 gene was not expressed in the PBMC. Our in vitro experiments showed that 17beta-oestradiol at concentrations of 10(-9) M and 10(-10) M decreased spontaneous IL-6 production by the PBMC of postmenopausal women. In vivo treatment with 17beta-oestradiol transdermally also significantly decreased spontaneous IL-6 production by the PBMC of postmenopausal women after 12 months of the therapy. Our results indicate that oestrogen deprivation after menopause may enhance IL-6 production by the PBMC of postmenopausal women. We suspect that the late complications of oestrogen deficiency, such as osteoporosis, coronary heart disease and Alzheimer's disease, may be mediated by an exaggerated production of IL-6 - a cytokine which seems to play a pivotal role in the pathogenesis of these age-related diseases.
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PMID:Effects of oestrogen deprivation on interleukin-6 production by peripheral blood mononuclear cells of postmenopausal women. 1183 56

Atherosclerotic plaques were likened histologically to healing inflammatory lesions by Russell Ross, who proposed a "response to injury" hypothesis for their formation. More recently, intraplaque inflammation has been postulated to play a role in thinning of the fibrous cap, plaque rupture, and superadded thrombosis. Potential causes for vascular injury include mechanical stress, smoke exposure, hypercholesterolemia, hyperhomocysteinemia, and chronic infection (direct, or indirect). Blood levels of inflammatory markers (e.g., C-reactive protein [CRP]; serum amyloid A [SAA]; fibrinogen; plasma viscosity; erythrocyte sedimentation rate [ESR]; leukocyte count, low serum albumin) have been associated with vascular risk factors and with prevalent and incident atherothrombotic cardiovascular disease (CVD) (coronary heart disease, [CHD]; stroke; and peripheral arterial disease). More recently, cytokines (e.g., interleukin-6 [IL-6]) and soluble adhesion molecules (e.g., intercellular adhesion molecule-1, vascular cell adhesion molecule-1) have been associated with both risk factors and disease; and offer potential therapeutic targets for nonspecific "anti-inflammatory" treatment of arterial disease. Infections associated with arterial disease include specific infections (Chlamydia pneumoniae, Helicobacter pylori) and nonspecific infections (periodontal infections, respiratory tract infections). Recent meta-analyses have shown that associations of serum markers of C. pneumoniae and H. pylori with arterial disease, risk factors, or potential intermediary mechanisms for disease are weaker than was first suggested by early reports. Likewise, further studies and meta-analyses are required to evaluate the epidemiologic relationships of CVD to periodontal infection and disease and to chronic pulmonary infections and disease. The weaker the associations between chronic infections and CVD, the larger is the size of randomized controlled trials required to establish (or exclude) a preventive effect of infection treatment. While control of chronic infection in the mouth, stomach or lungs is appropriate for its local effects, proving its efficacy in prevention of CVD presents a continuing challenge to medical science.
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PMID:The relationship between infection, inflammation, and cardiovascular disease: an overview. 1188 52

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