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)

High cholesterol is a well-established risk factor of myocardial infarction (MI). Since monocytes play a pivotal role in the development of atherosclerosis, one might anticipate that their functional properties are very important in relation to MI. In the present study, we have explored how the lipopolysaccharide (LPS)-induced reactivity of monocytes in whole blood in vitro relates to the serum lipid profile of healthy subjects with a history of MI or cancer in their close family. Twenty of the 54 subjects (of the total 266 test subjects) in the MI families had moderately high cholesterol (7.1-10.2 mmol/l), whereas 34 had normal cholesterol. Nineteen of the normocholesterol individuals had hyperactive monocytes (high responders), whereas 15 had monocytes responding normally. Two of the 20 subjects in the high cholesterol group had hyperactive monocytes. LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6 were on the average three to four times higher in the normocholesterol group compared with the moderately hypercholesterol group, and hence no positive correlation was found between hyperactive monocytes and cholesterol. The 42 subjects in the families with cancer had normal cholesterol, and two of these subjects had very high LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6, whereas eight of the 170 subjects without MI or cancer in their family were high responders. This further substantiates the notion that moderately high cholesterol is not associated with enhanced monocyte activation in whole blood. Hyperactive peripheral blood monocytes are suggested to be associated with a significant risk factor in developing coronary heart disease.
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PMID:Cellular activation responses in blood in relation to lipid pattern: healthy men and women in families with myocardial infarction or cancer. 1213 67

Cardiovascular pathology is the major cause of death in uraemia. There is evidence that a chronic inflammation with activation of C-reactive protein, interleukin-6, tumour necrosis factor-alpha and other cytokines is associated with vascular pathology, both in the general population and in dialysis patients. The cardiovascular system, and particularly the vascular wall, is the main target of the inflammatory process. Inflammation of the coronary arteries could be involved in the development of atherosclerosis and its related clinical syndromes. In the uraemic state, an increased production of pro-inflammatory cytokines may trigger the onset and progression of atherosclerosis and favour the subsequent complications, such as plaque fissuration and rupture. However, inflammatory cytokines also have a depressant action on the myocardium, thus inducing myocardial dysfunction. Together, these conditions may ultimately enhance the risk of myocardial infarction and death. From this standpoint, cardiovascular disease should also be investigated with the traditional biochemical inflammation markers and the evaluation of the circulating cytokine level, although new reliable markers could provide further diagnostic help. New therapeutic approaches should also be considered.
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PMID:Cardiac effects of chronic inflammation in dialysis patients. 1214 71

Inflammation is thought to play a central role in the aetiology and outcome of atherosclerosis. C-reactive protein (CRP) is a prominent product of the inflammatory response syndrome and a marker of overall and cardiovascular death in the general population and in dialysis patients. CRP is 5- to 10-fold higher in haemodialysis patients than in healthy controls and clearly is multifactorial in origin. A number of endogenous factors have been identified in vitro [angiotensin II, lipopolysacharide, modified low-density lipoprotein (LDL), advanced glycation end-products, homocysteine, viral infections] which all are able to trigger a nuclear factor (NF)-kappaB-mediated inflammatory, interleukin-6-driven, response via the generation of oxygen free radicals (oxidative stress). In addition, exogenous factors (dialysate endotoxin, vascular access, cuprophane dialyser material) have been identified in clinical studies which are also responsible, at least in part, for high serum CRP levels. Some of these factors function by themselves as non-traditional cardiovascular risk factors. Whether CRP is simply a marker of cardiovascular disease and mortality or whether it is in the causal pathway of the disease remains an open question. Recent data are in favour of a direct involvement in the pathogenesis of disease, since binding of CRP to degraded LDL enhances complement activation and induces the expression of tissue factor.
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PMID:C-reactive protein a marker for all-cause and cardiovascular mortality in haemodialysis patients. 1254 10

There is a lack of data on circulating levels of cell-adhesion molecules in relation to subclinical atherosclerosis measured in both the carotid and femoral arteries in humans. The aim of the present study was to investigate the relationship between clinically silent atherosclerosis and cell-adhesion molecules, and to explore the relationship between these molecules, C-reactive protein and the inflammatory cytokines interleukin-6, tumour necrosis factor-alpha (TNF-alpha), soluble TNF-alpha receptor p55 and soluble TNF-alpha receptor p75. The study group (n=391) consisted of clinically healthy 58-year-old men recruited from the general population. The results showed a positive trend between levels of soluble intercellular cell-adhesion molecule 1 (sICAM-1) and plaque occurrence in the carotid and femoral arteries (P=0.008), and also a univariate correlation between sICAM-1 levels and the composite variable of carotid and femoral intima-media thickness (P<0.001). When adjusted for other risk factors, the relationship between sICAM-1 and intima-media thickness no longer reached statistical significance. The level of sICAM-1 was associated with those of the pro-inflammatory cytokine TNF-alpha, its two soluble receptors, and also interleukin-6 and C-reactive protein. Levels of soluble E-selectin and vascular cell-adhesion molecule 1 (VCAM-1) showed weak or no association with subclinical atherosclerosis and inflammatory variables. Thus, in clinically healthy middle-aged men, levels of sICAM-1, but not of soluble VCAM-1 or E-selectin, were associated with both subclinical atherosclerosis and inflammatory variables.
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PMID:Circulating ICAM-1 (intercellular cell-adhesion molecule 1) is associated with early stages of atherosclerosis development and with inflammatory cytokines in healthy 58-year-old men: the Atherosclerosis and Insulin Resistance (AIR) study. 1214 2

Monocytes/macrophages (Mphi) play a pivotal role in the persistence of chronic inflammation and local tissue destruction in diseases such as rheumatoid arthritis and atherosclerosis. The production by Mphi of cytokines, chemokines, metalloproteinases and their inhibitors is an essential component in this process, which is tightly regulated by multiple factors. The peroxisome proliferator-activated receptors (PPARs) were shown to be involved in modulating inflammation. PPARgamma is activated by a wide variety of ligands such as fatty acids, the anti-diabetic thiazolidinediones (TZDs), and also by certain prostaglandins of which 15-deoxy-Delta(12,14)-PGJ2 (PGJ2). High concentrations of PPARgamma ligands were shown to have anti-inflammatory activities by inhibiting the secretion of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFalpha) by stimulated monocytes. The aim of this study was to determine whether PGJ2 and TZDs would also exert an immunomodulatory action through the up-regulation of anti-inflammatory cytokines such as the IL-1 receptor antagonist (IL-1Ra). THP-1 monocytic cells were stimulated with PMA, thereby enhancing the secretion of IL-1, IL-6, TNFalpha, IL-1Ra and metalloproteinases. Addition of PGJ2 had an inhibitory effect on IL-1, IL-6 and TNFalpha secretion, while increasing IL-1Ra production. In contrast, the bona fide PPARgamma ligands (TZDs; rosiglitazone, pioglitazone and troglitazone) barely inhibited proinflammatory cytokines, but strongly enhanced the production of IL-1Ra from PMA-stimulated THP-1 cells. Unstimulated cells did not respond to TZDs in terms of IL-1Ra production, suggesting that in order to be effective, PPAR ligands depend on PMA signalling. Basal levels of PPARgamma are barely detectable in unstimulated THP-1 cells, while stimulation with PMA up-regulates its expression, suggesting that higher levels of PPARgamma expression are necessary for receptor ligand effects to occur. In conclusion, we demonstrate for the first time that TZDs may exert an anti-inflammatory activity by inducing the production of the IL-1Ra.
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PMID:Regulation of the interleukin-1 receptor antagonist in THP-1 cells by ligands of the peroxisome proliferator-activated receptor gamma. 1216 May 20

It is now well established that vascular inflammation is an independent risk factor for the development of atherosclerosis. In otherwise healthy patients, chronic elevations of circulating interleukin-6 or its biomarkers are predictors for increased risk in the development and progression of ischemic heart disease. Although multifactorial in etiology, vascular inflammation produces atherosclerosis by the continuous recruitment of circulating monocytes into the vessel wall and by contributing to an oxidant-rich inflammatory milieu that induces phenotypic changes in resident (noninflammatory) cells. In addition, the renin-angiotensin system (RAS) has important modulatory activities in the atherogenic process. Recent work has shown that angiotensin II (Ang II) has significant proinflammatory actions in the vascular wall, inducing the production of reactive oxygen species, inflammatory cytokines, and adhesion molecules. These latter effects on gene expression are mediated, at least in part, through the cytoplasmic nuclear factor-kappaB transcription factor. Through these actions, Ang II augments vascular inflammation, induces endothelial dysfunction, and, in so doing, enhances the atherogenic process. Our recent studies have defined a molecular mechanism for a biological positive-feedback loop that explains how vascular inflammation can be self-sustaining through upregulation of the vessel wall Ang II tone. Ang II produced locally by the inflamed vessel induces the synthesis and secretion of interleukin-6, a cytokine that induces synthesis of angiotensinogen in the liver through a janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway. Enhanced angiotensinogen production, in turn, supplies more substrate to the activated vascular RAS, where locally produced Ang II synergizes with oxidized lipid to perpetuate atherosclerotic vascular inflammation. These observations suggest that one mechanism by which RAS antagonists prevent atherosclerosis is by reducing vascular inflammation. Moreover, antagonizing the vascular nuclear factor-kappaB and/or hepatic JAK/STAT pathways may modulate the atherosclerotic process.
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PMID:Vascular inflammation and the renin-angiotensin system. 1217 84

It has recently been demonstrated that the marked increase in the systemic concentration of cytokine interleukin-6 (IL-6) seen with exercise originates from the contracting limb and that skeletal muscle cells per se are the likely source of the production. This review summarizes the possible mechanisms for activation and biological consequences of muscle-derived IL-6. It appears that intramuscular IL-6 is stimulated by complex signaling cascades initiated by both calcium (Ca2+) -dependent and -independent stimuli. It also seems likely that skeletal muscle produces IL-6 to aid in maintaining metabolic homeostasis during periods of altered metabolic demand such as muscular exercise or insulin stimulation. It may do so via local and/or systemic effects. This review also explores the efficacy that IL-6 may be used as a therapeutic drug in treating metabolic disorders such as obesity, type 2 diabetes, and atherosclerosis.
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PMID:Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. 1220 25

Inflammatory markers have been demonstrated to be associated with increased risk of cardiovascular events. In this setting, C-reactive protein (CRP) was shown to add predictive value to cholesterol levels. We investigated hypercholesterolemic patients and related their inflammatory variables and their coagulation state focusing on factor VII, a coagulation protein which plays an established role in thrombogenesis. We examined the relationship between factor VII clotting activity (FVIIc), FVII antigen (FVIIAg) and activated FVII (FVIIa) levels against CRP, interleukin-6 soluble receptor (IL-6sR), P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta(1) (TGF-beta(1)), in fifty-eight hypercholesterolemic subjects. Patients were subjected to 6-8 weeks of lipid lowering treatment with diet or diet plus pravastatin (40 mg/day). Univariate analysis showed that FVII levels were positively associated with CRP (FVIIAg: r=0.56, P<0.0001; FVIIc: r=0.57, P<0.0001; FVIIa: r=0.39, P<0.001) and IL-6sR (FVIIAg: r=0.59, P<0.0001; FVIIc: r=0.52, P<0.0001; FVIIa: r=0.47; P<0.001). CRP was still correlated, at the baseline, with FVIIAg and FVIIc levels after multiple stepwise regression analysis (FVIIAg: P<0.0001; FVIIc: P<0.0001, respectively) and with FVIIAg at the end of lipid lowering treatment (P<0.0001). Our data indicate that the FVII level is independently associated with inflammatory variables and suggest their pathophysiological link in hypercholesterolemic patients.
Atherosclerosis 2002 Nov
PMID:Association of factor VII levels with inflammatory parameters in hypercholesterolemic patients. 1220 82

Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression, but their role in inflammation and immunity is unknown. We demonstrate here that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages reveals reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibit the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase (COX)-2 and interleukin-6 (IL-6) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice. These findings identify LXRs as lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.
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PMID:Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. 1256 35

The endothelium participates in haemostasis, inflammation, blood pressure regulation and other physiological systems. Consequently, endothelial dysfunction has been related to hypertension, thrombosis and atherosclerosis. Both von Willebrand factor (vWF) and tissue-type plasminogen activator (t-PA) are synthesized by the endothelium and their plasma levels increased during endothelium activation or injury. So far, they are well-known markers of endothelial cell function. Many circumstances activate or damage the endothelium, such as viruses, bacterium and inflammation. Circulating vWF and t-PA were studied in 92 unselected human immunodeficiency virus-1 (HIV-1)-infected patients [27 patients with and 65 patients without acquired immunodeficiency syndrome (AIDS)] and correlated with plasma levels of pro-inflammatory cytokines (tumour necrosis factor-alpha, interleukin-6), viral load, CD4 T-cell count and infectious status. HIV-1-infected patients had significantly higher plasma levels of vWF (152 versus 90%), tumour necrosis factor-alpha (31.3 versus 9.0 pg/ml) and interleukin-6 (3.5 versus 1.9 pg/ml) but not t-PA (5.9 versus 4.2 ng/ml) than the control group. These two endothelial markers correlated significantly with viral load and interleukin-6 levels in HIV-1-infected patients. The highest levels of vWF and t-PA were found in patients with AIDS. In conclusion, endothelial cell perturbation is present in HIV infection and may be a consequence of different mechanisms such as viral load, cytokines and advanced diseases.
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PMID:Viral load and disease progression as responsible for endothelial activation and/or injury in human immunodeficiency virus-1-infected patients. 1254 23


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