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)

There is growing evidence that increased plasma concentrations of CRP strongly predict cardiovascular death in both non-renal and renal patient populations. The interleukin-6 (IL-6) system activity, which is the major mediator of the acute phase response, is often markedly up-regulated in uremic patients and has also been shown to predict outcome. This raises the issue of whether or not IL-6 per se may contribute to increased mortality from malnutrition and atherosclerotic cardiovascular disease in uremic patients. The causes of elevated IL-6 levels in the uremic circulation are not fully understood, although a number of factors prevalent in uremic patients, such as hypertension, adiposity, infections, and chronic heart failure may all contribute. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysate, may stimulate IL-6 production. Furthermore, available evidence suggests that genetic factors may also have an impact on circulating plasma IL-6 levels. We advance the hypothesis that IL-6 may play a central role in the genesis of inflammatory-driven malnutrition and that it may be regarded as a significant proatherogenic cytokine. This hypothesis may provide a rationale to test if targeted anti-cytokine therapy may be one way to combat the unacceptable high cardiovascular mortality rate among dialysis patients.
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PMID:Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6? 1198 23

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in the pathogenesis of stroke. A base pair substitution -174G/C in the promoter region of the IL-6 gene regulates IL-6 gene expression. We compared the prevalence of this polymorphism in patients with lacunar stroke and in an age- and sex-matched cohort of asymptomatic controls. Eighty-two patients with lacunar stroke and 82 asymptomatic controls were prospectively assessed and genotyped for the -174G/C polymorphism in the promoter region of the IL-6 gene. Demographics and vascular risk factors were recorded in both groups. A brain computed tomography scan/magnetic resonance imaging confirmed the clinical diagnosis of lacunar stroke in all patients. The prevalence of CC genotype (18.3 vs. 7.3%, P=0.03), and the frequency of C allele (42.7 vs. 31.1%, P=0.03) were statistically significantly higher in patients with lacunar stroke than in asymptomatic controls. Expectedly, patients with lacunar stroke had a higher prevalence of vascular risk factors than asymptomatic controls. A logistic regression model showed that independent variables associated with lacunar stroke included history of hypertension (odds ratio (OR), 7.02; 95% confidence interval (95% CI), 3.11-15.81), diabetes (OR, 5.37; 95% CI, 1.52-8.89), hyperlipidemia (OR, 3.43; 95% CI, 1.04-11.25), smoking (OR, 5.84; 95% CI, 2.15-15.84), and CC genotype of the -174G/C IL-6 gene polymorphism (OR, 4.28; 95% CI, 1.22-15.00). These findings suggest that lacunar stroke might result from genetic susceptibility to inflammation-mediated damage in concert with atherosclerotic risk factors.
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PMID:A -174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction. 1198 87

Angiotensin II (Ang II), the most important component of the renin-angiotensin system, is usually associated with hypertension and renal failure. Through its pro-inflammatory actions, it also plays an important role in each step of the development of atherosclerotic plaques and plaque rupture. Ang II stimulates the expression of nuclear factor-kappaB (NFkappaB), a transcription factor which regulates gene expression of inflammatory cytokines such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Ang II type 1 receptors (AT1) and angiotensin converting enzyme (ACE) are dramatically increased in atherosclerotic plaques, particularly in monocytes at the fibrous cap. Thus, in multiple ways, Ang II is a critical factor in atherosclerotic plaque formation, inflammation and plaque stability. ACE inhibitors and AT1R inhibitors could therefore be appropriate therapeutic agents in the treatment of atherosclerosis.
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PMID:Angiotensin II as a pro-inflammatory mediator. 1209 Jul 26

Hypertension is a serious health problem in Western society, in particular for the African-American population. Although previous studies have suggested that the angiotensinogen (AGT) gene locus is involved in human essential hypertension, the molecular mechanisms involved in hypertension in African-Americans remain unknown. We show that an A/G polymorphism at -217 in the promoter of the AGT gene plays a significant role in hypertension in African-Americans. The frequency of the -217A allele was increased significantly in African-American hypertensive subjects compared with normotensive controls. We also show that the nucleotide sequence of this region of the AGT gene promoter bound strongly to CAAT/enhancer-binding protein (C/EBP) family transcription factors when nucleoside A was present at -217. In addition, we show that reporter constructs containing the human AGT gene promoter with nucleoside A at -217 had increased basal transcriptional activity upon transient transfection in HepG2 cells compared with reporter constructs with nucleoside G at -217. Finally, we show that interleukin-6 treatment in the presence or absence of overexpressed C/EBPbeta increased the promoter activities of reporter constructs containing nucleoside A at -217 compared with reporter constructs containing nucleoside G at -217. Because the AGT gene is expressed primarily in liver and adipose tissue, and C/EBP family transcription factors play an important role in gene expression in these tissues, we propose that increased transcriptional activity of the -217A allele of the human AGT gene is associated with hypertension in African-Americans.
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PMID:Angiotensinogen gene polymorphism at -217 affects basal promoter activity and is associated with hypertension in African-Americans. 1214 90

We evaluated the effect of different peroxynitrite scavengers for adjunctive therapy of experimental bacterial meningitis. Twenty hours after intracisternal injection of Streptococcus pneumoniae, rats were treated with ceftriaxone [100 mg/kg intraperitoneal (i.p.)] and either urate (300 mg/kg i.p.), Mn(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP, 15 mg/kg i.p.), ascorbate (100 mg/kg i.p.), or urate (300 mg/kg i.p.) + ascorbate (100 mg/kg i.p.). Six hours after initiation of treatment, the cerebrospinal fluid (CSF) pleocytosis was significantly (p<0.05) reduced by urate (8697 +/- 1526 cells/microl) and MnTBAP (8542 +/- 4059 cells/microl) vs. ceftriaxone alone (15,793 +/- 3202 cells/microl). Brain concentrations of proinflammatory cytokines [interleukin-1beta (IL-beta), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2)] were also reduced by urate and MnTBAP. The intracranial hypertension was significantly reduced by MnTBAP (14.0 +/- 5.4 mm Hg), but not by urate (25.5 +/- 7.1 mm Hg) vs. ceftriaxone alone (22.5 +/- 5.9 mm Hg). Ascorbate alone had no effect on CSF pleocytosis (15,775 +/- 7058 cells/microl), intracranial pressure (25.6 +/- 8.8 mm Hg), and brain cytokine concentrations. However, the combination of urate and ascorbate was as effective as MnTBAP (CSF pleocytosis: 5392 +/- 4232 cells/microl, intracranial pressure: 13.3 +/- 6.9 mm Hg).
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PMID:Pneumococcal meningitis in the rat: evaluation of peroxynitrite scavengers for adjunctive therapy. 1216 22

This study was undertaken to review the links between maternal nutrition, offspring's birth weight and the propensity to early insulin resistance and high diabetes rates in Indian adults. Studies included a comparison of maternal size and nutrition with birth weights in Pune, India, and Southampton, UK. In Pune, the growth, insulin resistance and blood pressure of four-year-old children were assessed. Adults >40 years of age, who were resident in rural areas, were compared with adults living in urban areas for size, glucose handling, lipid status and blood pressure. Newly diagnosed diabetic adults living in urban areas were also monitored. Height, weight, head, waist and hip circumferences, skin-fold measurements and blood pressure were routinely measured. Fasting glucose, insulin, total and high-density lipoprotein cholesterol and triglycerides were linked to the glucose and insulin responses during glucose tolerance tests. Cytokine levels were measured in plasma samples of urban and rural adults. Indian babies were lighter, thinner, shorter and had a relatively lower lean tissue mass than the Caucasian babies. However, the subcutaneous fat measurements of these babies were comparable to those of the white Caucasian babies. The Indian mothers were small, but relatively fat mothers produced larger babies. Maternal intake of green vegetables, fruit and milk, and their circulating folate and vitamin C levels, predicted larger fetal size. Rapid childhood growth promoted insulin resistance and higher blood pressure. Rural adults were thin, with a 4% prevalence of diabetes and a 14% prevalence of hypertension, but the risks increased within the normal body mass index (BMI) range. Type 2 diabetes was common in urban adults younger than 35 years of age. Although the average BMI was 23.9 kg m(-2), central obesity and thin limbs were noteworthy. Levels of interleukin-6 and tumour necrosis factor-a were markedly increased in urban dwellers. Hence, there is evidence of a remarkably powerful, intergenerational effect on body size and total and central adiposity. Indians are highly susceptible to insulin resistance and cardiovascular risks, with babies being born small but relatively fat. Insulin resistance is amplified by rapid childhood growth. Dietary factors seem to have profound long-term metabolic influences in pregnancy. Overcrowding with infections and central obesity may amplify cytokine-induced insulin resistance and early diabetes in Indian adults with a low BMI.
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PMID:The lifecycle effects of nutrition and body size on adult adiposity, diabetes and cardiovascular disease. 1216 75

Several studies have proposed a relationship between blood pressure and inflammation. Interleukin-6 (IL-6) is a multifunctional cytokine involved in inflammation and tissue injury and potentially influencing blood pressure. Recently, a common polymorphism of the IL-6 gene, associated with differences in the transcription rate of the protein, has been described. The aim of this study was to investigate a possible association between genetic variations of the -174GC polymorphism of the IL-6 gene promoter and hypertension in humans. IL-6 gene promoter polymorphism was evaluated by polymerase chain reaction followed by restriction enzyme analysis in 210 elderly Italian patients affected by essential hypertension (EH) and 177 age- and sex-matched controls. The distribution of IL-6 genotypes was 85 GG, 88 GC, 37 CC in the hypertensive patients and 65 GG, 73 GC, 39 CC in the control subjects. In this elderly cohort, no statistically significant association was found between the two groups (P = 0.45 for GG homozygous, P = 0.89 for GC heterozygous and P = 0.27 for CC homozygous). In conclusion the -174 GC polymorphism of the IL-6 gene promoter is not a marker for EH in this sample of elderly Italians.
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PMID:The -174 G/C polymorphism of the interleukin-6 gene promoter and essential hypertension in an elderly Italian population. 1221 60

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

The low affinity A(2B) adenosine receptor, like any other adenosine receptor subtype, belongs to the super-family of seven transmembrane domain protein-coupled receptors (7TMs GPCR) and is classified by the GPCR database in the family of rhodopsin like receptors (Class A of GPCR). It has been cloned from various species, including rat and human, and its sequences are highly similar across species, ranging from 85% identity between human and mouse and 95% identity between rat and mouse. The A(2B)receptors show a ubiquitous distribution, the highest levels are present in cecum, colon and bladder, followed by blood vessels, lung, eye and mast cells. Through A(2B) receptors adenosine seems to cause mast cells degranulation, vasodilation, cardiac fibroblast proliferation, inhibition of Tumor Necrosis Factor (TNF-alpha), increased synthesis of interleukin-6 (IL-6), stimulation of Cl(-) secretion in intestinal epithelia and hepatic glucose production. Hence, A(2B) adenosine receptor agonists could be useful in the treatment of cardiac diseases like hypertension or myocardial infarction and in the management of septic shock, while antagonists may serve as novel drugs for asthma, Alzheimer's disease, cystic fibrosis and type-II diabetes. No potent and selective A(2B) agonists have been reported so far; 5'-N-ethylcarboxamidoadenosine (NECA) is one of the most active. The monosubstitution on N(6)-position of adenosine is well tolerated and that position appears to be a useful site for increasing A(2B) potency. Among substituents in 2-position of adenosine only 1-alkynyl chains are effective for A(2B) potency. In particular, the (S)-2-hydroxypropynyl substituents brought about the highest activity demonstrating that the A(2B) receptors discriminate between (R) and (S) diastereomers. Hence, (S)-2-phenylhydroxypropynylNECA (PHPNECA), with an EC(50) = 0.22 micro M, proved to be the most potent A(2B) agonist reported so far. Classical antagonists for adenosine receptors are alkylxanthines which show considerable potency at A(2B) receptors. Para substituted 1,3-dialkyl-8-phenylxanthines possess high affinity in binding assays; the 3-unsubstituted 1-alkyl analogues resulted more A(2B) selective with the 8-[4-[(N-(2-hydroxyethyl)carboxamidomethyl)oxy]phenyl]-1-propylxanthine (60) showing the highest affinity (K(i) = 1.2 nM) and selectivity (A(1)/A(2B) = 60, A(2A)/A(2B) = 1,790, A(3)/A(2B) = 360). Among non-xanthine derivatives very promising are substituted purines, in which combination of appropriate substituents in 2-, 8-, and 9-position could lead to very potent and selective A(2B) antagonists.
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PMID:Medicinal chemistry and pharmacology of A2B adenosine receptors. 1257 Jul 60

In spite of its high impact on cardiovascular and renal disease, knowledge on risk factors for the development of high blood pressure (HBP) is limited. Mild chronic inflammation may play a significant role in the incidence of HBP. A persistent low-grade inflammation state could be associated with high but within the 'normal range' cytokine plasma concentration. By impairing the capacity of the endothelium to generate vasodilating factors, particularly nitric oxide (NO), elevated cytokines may lead to the development of endothelial dysfunction, chronic impaired vasodilation, and HBP. These alterations in the L-arginine : NO pathway may play a major role in the development of HBP in young subjects, with inflammation-related alterations in the production of cyclo-oxygenase-derived vasoconstrictors becoming more prominent with advanced age. Cross-sectional independent associations between HBP and plasma levels of C-reactive protein, interleukin-6, and tissue necrosis factor alpha have been reported, but no prospective evidence of these associations is currently available.
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PMID:Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence. 1269 66


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