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)

Monocytes/macrophages (Mo) appear to play a critical role in the initiation and progression of atherosclerotic lesions. In this study, we characterized in vitro-differentiated embryonic stem (ES) cell macrophages as a model system for studying atherosclerosis-associated Mo functions. Using immunofluorescence staining and Western analysis, we demonstrate that ES Mo express typical macrophage cell surface markers, as well as the known receptors for modified forms of low density lipoprotein (LDL), including the Mo scavenger receptors (SR-A type I and type II), CD36, and CD68. Differentiated ES Mo specifically bind and degrade 125I-labeled acetylated LDL with high affinity, and their incubation with acetylated LDL (15 microg/mL) for 48 hours produces characteristic "foamy" Mo, as visualized by oil red O staining. ES Mo also express matrix-degrading metalloproteinases (MMP-3, MMP-9), which have been implicated in collagen breakdown in the fibrous cap of atherosclerotic plaques, and secrete cytokines (tumor necrosis factor-alpha, interleukin-6) in response to inflammatory stimuli. Transfection experiments, using a green fluorescent protein reporter gene, driven by the myeloid-specific promoter, CD11b, demonstrated that ES Mo can also be used to study macrophage-restricted gene expression in vitro. Taken together, these data demonstrate that ES Mo exhibit many properties typical of arterial lesion macrophages. Its ease of genetic manipulation makes it an attractive system for investigations of macrophage functions in vitro.
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PMID:In vitro-differentiated embryonic stem cell macrophages: a model system for studying atherosclerosis-associated macrophage functions. 976 39

During active disease, patients with systemic-onset juvenile chronic arthritis (S-JCA) demonstrate a rise and fall in serum interleukin-6 (IL-6) that parallels the classic quotidian fever. To investigate the possibility that this cytokine profile results from a difference in the control of IL-6 expression, we examined the 5' flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism was detected at position -174. In a group of 383 healthy men and women from a general practice in North London, the frequency of the C allele was 0.403 (95% confidence interval 0.37-0.44). In comparison, 92 patients with S-JCA had a different overall genotype frequency, especially those with onset of disease at < 5 yr of age. This was mainly due to the statistically significant lower frequency of the CC genotype in this subgroup. When comparing constructs of the 5' flanking region (-550-+61 bp) in a luciferase reporter vector transiently transfected into HeLa cells, the -174C construct showed 0.624+/-0.15-fold lower expression than the -174G construct. After stimulation with LPS or IL-1, expression from the -174C construct did not significantly change after 24 h, whereas expression from the -174G construct increased by 2.35+/-0.10- and 3.60+/-0.26-fold, respectively, compared with the unstimulated level. Plasma levels of IL-6 were also measured in 102 of the healthy subjects, and the C allele was found to be associated with significantly lower levels of plasma IL-6. These results suggest that there is a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. The reduced frequency of the potentially protective CC genotype in young S-JCA patients may contribute to its pathogenesis. Similarly the individual's IL-6 genotype may be highly relevant in other conditions where IL-6 has been implicated, such as atherosclerosis.
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PMID:The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. 976 29

Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, alpha-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acute-phase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair.
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PMID:Is type II diabetes mellitus a disease of the innate immune system? 1023 Jun 57

High plasma fibrinogen appears to be an important risk factor for the development of atherosclerosis. The aim of our study was to measure fibrinogen and fibrin degradation products (D-dimer), interleukin-6 tissue plasminogen activator, plasminogen activator inhibitor-1 and urokinase-type plasminogen activator in the plasma and arterial walls of 45 patients who had arterial surgery between April 1993 and November 1995. The arterial specimens were also examined by immunohistochemists for these same factors. The serum fibrinogen and fibrin degradation products were high in all patients, and fibrinolysis was depressed. Few leukocytes were seen in the arterial walls, which had poor fibrinolytic activity. Plasminogen-activator inhibitor activity in the wall was also reduced in the affected arterial walls. The abdominal aorta appeared to have the highest levels of fibrinogen and this may be related to its ability to form aneurysms. Fibrinogen may play an important role in the progression of atherosclerotic disease.
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PMID:Fibrinogen and fibrinolysis in blood and in the arterial wall: its role in advanced atherosclerotic disease. 979 64

Disruption of atherosclerotic plaques with associated thrombus is responsible for the majority of the acute coronary syndromes. Plaque instability is related closely to the degree of inflammation. Inflammatory cells within the plaque produce cytokines that inhibit collagen production by vascular smooth muscle cells and increase the production of metalloproteinases, which degrade the extracellular matrix in the fibrous cap. The recruitment of inflammatory cells into the vessel wall occurs in a coordinated sequence of events involving the expression of cellular adhesion molecules on the surface of activated endothelial cells and the production of chemoattractants, and occurs in part in response to oxidation of low-density lipoprotein within the vessel wall. The cellular adhesion molecules are shed into the circulating blood in several disease states, including clinically evident atherosclerosis. The acute-phase reactants C-reactive protein and interleukin-6, and markers of the fibrinolytic state (plasminogen activator inhibitor-1 and tissue plasminogen activator), are also elevated in the acute coronary syndromes and in healthy individuals at increased risk for developing coronary artery disease. These markers may reflect vascular inflammation and thereby the stability of atherosclerotic plaques. Their measurement may pinpoint the mechanisms of benefit of cholesterol-lowering therapy and other interventions designed to reduce coronary risk, and potentially could offer a new method for monitoring coronary risk factor reduction in patients.
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PMID:Inflammation, the endothelium, and the acute coronary syndromes. 988 50

GH deficiency (GHD) is associated with increased prevalence of atherosclerosis and cardiovascular morbidity. Because monocytes play a crucial role in the development of atherosclerosis, we investigated in the present study the effect of GH deficiency and subsequent GH replacement on monocytic function in hypopituitary subjects. Twelve patients were randomized to receive GH replacement therapy (either 3 or 6 microg/kg x day, s.c.) for 3 months. Plasma levels and monocyte production of cytokines and monocyte adhesion to endothelium were determined in controls and patients with GHD before and after GH treatment. Before GH therapy, patients with GHD had increased basal plasma tumor necrosis factor-alpha (TNF alpha; 220% over control values; P = 0.004) and interleukin-6 (IL-6; 340% over control values; P 0.0009) levels. Basal monocyte production of both cytokines was also significantly higher in patients with GHD [484% over control values for TNF alpha (P = 0.0007); 1479% over control values for IL-6 (P = 0.035)]. GH treatment for 3 months led to a reduction in plasma TNF alpha (135% over control values; P = 0.03, pre- vs. post-GH therapy), monocyte TNF alpha production (204% over control values; P = 0.01), plasma IL-6 (219% over control values; P = 0.07), and monocyte IL-6 production (448% over control values; P = 0.01). Plasma TNF alpha levels positively correlated with monocyte TNF alpha production in patients with GHD both before and after GH therapy (P = 0.003 and P = 0.049, respectively). A positive correlation (P = 0.0003) was also observed between monocyte TNF alpha production and monocyte IL-6 production. There were no correlations between these plasma cytokine levels or monocyte cytokine production and parameters of body composition, lipid profile, or IGF-I and IGF-binding protein-3 levels. Before GH treatment, adhesiveness of monocytes to cultured aortic endothelial cells was also enhanced. This alteration was not reversed by GH administration. In conclusion, our results demonstrate that markers of monocyte activation are increased in patients with GHD and that GH replacement partly reduces these abnormalities. Reduction of cellular activation of monocytes by GH therapy could potentially contribute to reduce the risk of cardiovascular events in patients with GHD.
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PMID:Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy. 1048 24

Multiple data suggest that the renin-angiotensin system contributes to the pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin system can only in part be explained by the influence of its effector angiotensin II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic activity. Because chronic inflammation of the vessel wall is a hallmark of atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin. Inflammatory activation was assessed by determination of interleukin-6 (IL-6) release into the culture medium, detection of IL-6 mRNA by RT-PCR, and demonstration of activation of nuclear factor-kappaB in electrophoretic mobility shift assays. Angiotensin II concentration-dependently (1 nmol/L to 1 micromol/L) stimulated IL-6 production by SMCs via activation of the angiotensin II type 1 receptor (demonstrated by the inhibitory action of the receptor antagonist losartan). Angiotensin I increased IL-6 production by SMCs, too. This effect was inhibited by captopril and ramiprilat, suggesting conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme in SMCs. Steady-state mRNA for IL-6 was augmented after stimulation with angiotensin II, suggesting regulation of angiotensin-induced IL-6 release at the pretranslational level. Moreover, the proinflammatory transcription factor nuclear factor-kappaB, which is necessary for transcription of most cytokine genes, was also activated by angiotensin II. Pyrrolidine dithiocarbamate suppressed angiotensin II-induced IL-6 release, a finding compatible with involvement of reactive oxygen species as second messengers in cytokine production mediated by angiotensin. The data demonstrate the ability of angiotensin to elicit an inflammatory response in human vascular SMCs by stimulation of cytokine production and activation of nuclear factor-kappaB. Inflammatory activation of the vessel wall by a dysregulated renin-angiotensin system may contribute to the pathogenesis of atherosclerosis.
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PMID:Angiotensin induces inflammatory activation of human vascular smooth muscle cells. 1039 79

Atherosclerosis, the main lethal disease in the Western world, is associated with a cellular immune response in the arterial lesions and a humoral immune response directed towards oxidized lipoproteins, certain microbes and other antigens. The local immune response is dominated by macrophages and T cells, while to date, the role of B cells in lesions has been unclear. We analysed B-cell involvement in lesions using the apolipoprotein E knockout mouse, an experimental model that develops accelerated atherosclerosis when fed a lipid-rich diet. Both early fatty-streak-type lesions and full-blown atherosclerotic plaques of these mice contained CD22+ B cells. They accumulated predominantly in the base of lesions, where high expression levels of vascular cell adhesion molecule-1 (VCAM-1) were observed in other cells. Cells expressing interleukin-6 and tumour necrosis factor-alpha were also detected and IgM was abundant in this region. These data show that B cells participate in atherosclerosis in this experimental model; the data also suggest that these cells may accumulate through VCAM-1 expression by surrounding cells and may produce antibodies and proinflammatory cytokines. These factors are likely to be important in the pathogenesis of atherosclerosis.
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PMID:Detection of B cells and proinflammatory cytokines in atherosclerotic plaques of hypercholesterolaemic apolipoprotein E knockout mice. 1040 48

Recent studies suggest that atherosclerosis is a kind of inflammatory process and that cytokine plays important roles in this process. Although it is generally accepted that angiotensin II (Ang II) plays an important role in atherogenesis, the role of Ang II in cytokine production has not been explored. In this report, we investigated the effect of Ang II on the production of interleukin-6 (IL-6), which is a multifunctional proinflammatory cytokine in rat vascular smooth muscle cells. Ang II significantly increased the expression of IL-6 mRNA and protein in a dose-dependent manner (10(-10) to 10(-6) mol/L). The expression of IL-6 mRNA induced by Ang II showed 2 peaks at 30 minutes and 12 to 24 hours after stimulation. The effect of Ang II on IL-6 release and mRNA expression was completely blocked by an Ang II type 1 receptor antagonist, CV11974; however, an Ang II type 2 receptor antagonist, PD123319, showed no effect. Chelating of intracellular Ca(2+) with BAPTA-AM, inhibition of tyrosine kinase with genistein, and inhibition of mitogen-activated protein kinase kinase with PD98059 completely abolished the effect of Ang II. However, downregulation of protein kinase C by pretreatment with a phorbol ester for 24 hours or a specific protein kinase C inhibitor, calphostin C, did not affect the Ang II-induced expression of IL-6 mRNA. Deletion and mutational analysis of IL-6 gene promoter showed that cAMP-responsive element was important for Ang II-induced IL-6 gene expression. Gel mobility shift assay showed an increase of cAMP-responsive element binding protein by Ang II. These results provide new insights into Ang II signaling and the role of Ang II in the progression of inflammatory changes of blood vessels.
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PMID:Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells. 1040 34

Inflammatory phenomena at sites of atherosclerotic plaques are increasingly thought to be major determinants of the progression and clinical outcome of atherosclerotic disease. Therefore, attention is being paid to systemic markers/mediators which may reflect the inflammatory activity in the plaques. This study evaluates the pattern of the main proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), their soluble receptors/antagonist, and a variety of inflammatory markers, in patients with peripheral arterial disease (PAD). Eight patients with PAD suffering from claudicatio intermittens (CI), eight with critical limb ischemia (CLI) and eight controls (C) were studied. Blood samples were collected at baseline in all groups and. for C and CI, immediately after and 4 h after a 30-min treadmill test. Baseline: no differences in cytokine plasma levels were detected among the three groups. In contrast, soluble receptors of TNF (type I and II) and of IL-6, and IL-1beta receptor antagonist (IL-1ra) were increased in CI and CLI patients, as compared to C. Of note, IL-Ira correlated with the occurrence and stage of the disease in a highly significant proportion of the patients, reaching a predictive value for the disease of P < 0.0001. The opposite trend was observed for the soluble receptor of IL-1beta. Notably, in the patients no alterations could be found in white blood cell counts, expression of CD11c adherence molecule by circulating monocytes or, in vitro. O2- release from zymosan-activated neutrophils. Moreover, plasma levels of platelet activating factor (PAF), of neutrophil elastase and of the acute phase reactants C-reactive protein (CRP) and alpha1-acid glycoprotein were not found to be significantly altered. In contrast, the acute-phase proteins alpha1-antitrypsin (alpha1AT) and haptoglobin (HG) were found to be increased. Effect of treadmill: IL-1beta and TNFalpha remained at baseline levels following exercise, and IL-6 dropped to undetectable levels. Among cytokine antagonists, again the most relevant changes concerned the IL-1ra, which was significantly increased immediately after the treadmill test, both in CI and C, and returned to baseline levels after 4 h. In contrast, soluble TNFalpha, IL-1beta and IL-6 receptors, PAF, and the other markers of leukocyte activation were not found to be altered. Soluble TNFalpha and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase proteins alpha1AT and HG have been reported to exert anti-inflammatory functions. The increased plasma levels of these agents, together with low levels of inflammatory cytokines and other pro-inflammatory mediators such as PAF and alpha1-acid glycoprotein, appear to draw an undescribed picture, so far, of upregulation of a composite systemic anti-inflammatory mechanism in atherosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for developing new insights into the pathogenesis of the atherosclerotic disease.
Atherosclerosis 1999 Jul
PMID:Atherosclerosis and inflammation. Patterns of cytokine regulation in patients with peripheral arterial disease. 1042 95

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