Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic exposure is associated with an increased risk of vascular disorders, and results in increased oxidative stress in endothelial cells and vascular smooth muscle cells (VSMCs). Since oxidative stress is involved in regulating the expression of genes related to atherogenesis, we investigated its involvement in the enhanced expression of three atherosclerosis-related genes coding for heme oxygenase-1 (HO-1), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in VSMCs treated with inorganic sodium arsenite (iAs). In human VSMCs (hVSMCs) and rat VSMCs (rVSMCs), HO-1, MCP-1, and IL-6 mRNA levels were significantly increased by iAs treatment. An increase in HO-1 protein levels in hVSMCs was confirmed by Western blotting technique, while increased MCP-1 and IL-6 secretion by hVSMCs was demonstrated by enzyme-linked immunosorbent assay. Although modulators of oxidative stress inhibited this iAs-induced increase in the expression of these three genes, different modulators had differential effects. In iAs-treated rVSMCs, catalase, dimethylsulfoxide, and L-omega-nitro-L-arginine significantly inhibited the increase in expression of all three genes, allopurinol inhibited the increase in MCP-1 and IL-6 expression, but had no effect on HO-1 expression, while superoxide dismutase had no significant effect on HO-1 expression, but had an inhibitory effect on IL-6 expression and a stimulatory effect on MCP-1 expression. Therefore, iAs may enhance the expression of HO-1, MCP-1, and IL-6 in VSMCs via different reactive oxygen molecules. Furthermore, using tin protoporphyrin IX (SnPP) and anti-MCP-1 antibody to abolish iAs-induced HO-1 and MCP-1 activity, respectively, shows that HO-1 has protective effect against iAs-induced injury in VSMCs and MCP-1 is chemoattractive to human monocytes, THP-1.
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PMID:Oxidative stress mediates sodium arsenite-induced expression of heme oxygenase-1, monocyte chemoattractant protein-1, and interleukin-6 in vascular smooth muscle cells. 1568 17

The activation and function of c-Jun N-terminal kinases (JNKs) were investigated in primary microglia cultures from neonatal rat brain, which express all three JNK isoforms. Lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and thrombin preparations induced a rapid and lasting activation of JNKs in the cytoplasm. In the nucleus, the activation patterns were rather complex. In untreated microglia, the small pool of nuclear JNKs was strongly activated, while the high-affinity JNK substrate c-Jun was only weakly phosphorylated. Stimulation with LPS increased the total amount of nuclear JNKs and the phosphorylation of the transcription factor c-Jun. Levels of activated JNKs in the nucleus, however, rapidly decreased. Analysis of the nuclear JNK isoforms revealed that the amount of JNK1 declined, while JNK2 increased, and the weakly expressed JNK3 did not vary. This observation suggests that JNK2 is mainly responsible for the activation of c-Jun in this context. Upstream of JNKs, LPS induced a lasting activation of the constitutively present JNK kinase MKK4. The function of JNKs in LPS-triggered cellular reactions was investigated using SP600125 (0.5-5 microM), a direct inhibitor of JNKs. Inhibition of JNKs reduced the LPS-induced metabolic activity and induction of the AP-1 target genes cyclooxygenase-2 (Cox-2), TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in response to LPS, while ERK1/2 and p38 alpha had a more pronounced effect on LPS-induced cellular enlargement than JNKs. In summary, JNKs are essential mediators of relevant pro-inflammatory functions in microglia with different contributions of the JNK isoforms.
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PMID:c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. 1573 88

Interleukin-6 (IL-6), the major proinflammatory cytokine, has been described to be associated with the hypertensive and atherosclerotic states. We aimed to explore whether the concentration of circulating IL-6 and adhesion molecules could be modified by decreasing blood pressure in hypertensive subjects. A total of 30 subjects (18 men), aged 34-48 years, were enrolled in this study, 17 hypertensive never-treated patients (HTA) and 13 normotensive subjects (C). HTA subjects were treated with irbesartan, 150-300 mg/day for 3 months, and serum IL-6, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, sP-selectin, sE-selectin and monocyte chemoattractant protein-1 were measured at 0 and 12 weeks. The two study groups were similar in age, body mass index (BMI) and gender. At baseline, circulating IL-6 levels, but not adhesion molecules, were significantly associated with systolic blood pressure (r=0.41; P=0.03) and BMI (r=0.53; P=0.005). Systolic and diastolic blood pressure decreased significantly (P<0.01) in parallel to serum IL-6 levels (from 3.72+/-0.82 to 3.23+/-0.19 pg/ml, P=0.02) reaching a similar concentration to normotensive patients (3.33+/-0.3 pg/ml) after treatment with irbesartan. No significant changes were observed in any other of the tested parameters. In conclusion, the treatment of high blood pressure lowers circulating IL-6 in young hypertensive patients.
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PMID:Lowering of blood pressure leads to decreased circulating interleukin-6 in hypertensive subjects. 1575 24

To investigate the effect of proinflammatory cytokines on spiral ligament (SL) fibrocytes and regulation of cytokines by dexamethasone (Dex), in vitro studies were performed in murine secondary cell cultures. Cultured SL fibrocytes were stimulated with tumor necrosis factor-alpha (TNF-alpha), and the secretion of various mediators was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcribed-polymerase chain reaction (RT-PCR). After stimulation with TNF-alpha, levels of keratinocyte-derived cytokine (KC), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) were elevated in the culture supernatant, and their corresponding messenger RNAs were detected in the cultured fibrocytes. When the cultures were incubated with both TNF-alpha and Dex, the levels of KC, MCP-1, MIP-2 and IL-6 were significantly lower than those in cultures treated with TNF-alpha alone. The data suggest that Dex suppresses the inflammatory response in SL fibrocytes. Given that SL fibrocytes play a role in cochlear fluid and ion homeostasis, glucocorticoids may suppress the cochlear malfunction caused by SL inflammation.
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PMID:Dexamethasone inhibits tumor necrosis factor-alpha-induced cytokine secretion from spiral ligament fibrocytes. 1581 7

The aim of the study was to determine whether a short-term treatment with simvastatin or fenofibrate may result in beneficial anti-inflammatory and antithrombotic effects in patients with high risk of coronary artery disease. In a randomized, double-blind study, we compared markers of inflammation, thrombin formation and platelet activation in patients with LDL cholesterol >130 mg/dl assigned to receive simvastatin (40 mg/d; n=20) or micronised fenofibrate (160 mg/d; n=22) for 28 days. Simvastatin, but not fenofibrate, lowered C-reactive protein (CRP) by 32% on day 3 (p<0.001), while both drugs reduced CRP significantly on day 28. Interleukin-6, soluble CD40 ligand, and monocyte chemoattractant protein-1 levels decreased significantly (by 20 to 50%) in both treatment groups on days 3 and 28. Soluble cell adhesion molecules remained unchanged in both groups. Simvastatin and fenofibrate significantly lowered plasma concentrations of thrombin-antithrombin complexes on days 3 and 28, but not platelet beta-thromboglobulin (betaTG) levels. Soluble P-selectin was lowered only in the simvastatin group. The total amount of thrombin generated at the site of microvascular injury also declined (by about 30%) as early as after 3 days of fenofibrate or simvastatin therapy, whereas beta TG release was reduced only in the simvastatin group on days 3 and 28. All the effects were independent of the changes in lipid profiles. Our results suggest that statins and fibrates can exert antithrombotic and anti-inflammatory effects as early as after 3 days of therapy. However, in contrast to statins, fibrates have no influence on platelet function within one month of therapy.
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PMID:Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia. 1611 3

Proinflammatory cytokines and adhesion molecules expressed by endothelial cells (ECs) play a critical role in initiating and promoting atherosclerosis. Agents that oppose these inflammatory effects in vascular cells include peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands, including 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-gamma agonists, 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes, has been characterized. The purpose of this study was to evaluate the anti-inflammatory effects of two PPAR-gamma-active members of this class, 1,1-bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) and 1,1-bis(3'-indolyl)-1-(p-biphenyl)methane (DIM-C-pPhC(6)H(5)), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC(6)H(5), DIM-C- pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 microM, DIM-C-pPhtBu and DIM-C-pPhC(6)H(5) decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 microM 15d-PGJ2 (p < 0.05). In contrast, 10 microM ciglitazone and DIM-C-pPhCH(3), which exhibits low PPAR-gamma agonist activity, were inactive. The two new PPAR-gamma agonists and 15d-PGJ2 also inhibited TNF-alpha-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-alpha-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH(3) did not decrease TNF-alpha-induced expression of these two proteins. This new structural class of PPAR-gamma agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-alpha-activated ECs at lower concentrations than other synthetic PPAR-gamma agonists, suggesting the potential clinical utility of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes for decreasing endothelial inflammation.
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PMID:Inhibition of tumor-necrosis-factor-alpha induced endothelial cell activation by a new class of PPAR-gamma agonists. An in vitro study showing receptor-independent effects. 1615 67

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers predict risk of cardiovascular disease (CVD). Thus, finding genes that influence systemic levels of inflammatory biomarkers may provide insights into genetic determinants of vascular inflammation and CVD. We conducted variance-component linkage analyses of blood levels of four biomarkers of vascular inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1)] in 304 extended families from the Framingham Heart Study, using data from a 10cM genome scan. We computed p-values by a permutation approach. Heritability estimates ranged from 14% (IL-6) to 44% (MCP-1) after log transforming and adjusting for covariates. Significant linkage to MCP-1 was found on chromosome 1 (LOD=4.27 at 186cM; genome-wide p=0.005), in a region containing inflammatory candidate genes such as SELE, SELP (E- and P-selectin) and CRP. Other linkage peaks with LOD scores >2 were found for MCP-1 on chromosome 1 (LOD=2.04 at 16cM; LOD=2.34 at 70cM) and chromosome 17 (LOD=2.44 at 22cM) and for sICAM-1 on chromosome 1 at 229cM (LOD=2.09) less than 5cM from the interleukin-10 (IL10) gene. Multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of CVD.
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PMID:Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q. 1615 3

Thrombospondin-1 (TSP-1) is a multifunctional, rapid-turnover matricellular protein. Recent studies demonstrated that TSP-1 has a role in regulating inflammatory reactions. Myocardial infarction (MI) is associated with an inflammatory response, ultimately leading to healing and scar formation. In particular, an enhanced inflammatory reaction and a massive accumulation of monocytes/macrophages is seen with reperfusion after MI. To examine the role of TSP-1 in MI, we isolated rat TSP-1 complementary DNA (cDNA) and analyzed the level and distribution of the mRNA expression. In infarcted rat hearts, TSP-1 mRNA increased markedly at 6 and 12 hrs after coronary artery ligation (27.97 +/- 3.40-fold and 22.77 +/- 1.83-fold, respectively, compared with sham-operated hearts). Western blot analysis revealed that TSP-1 protein was transiently induced in the infarcted heart. Using in situ hybridization analysis, TSP-1 mRNA signals were observed in the infiltrating cells at the border area of infarction. We then examined the effect of ischemia/reperfusion (I/R) on TSP-1 mRNA induction in the rats with infarcted hearts. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that I/R enhanced the TSP-1 mRNA expression approximately 4-fold, as compared with the level in the permanently ligated heart. Finally, we examined the effect of TSP-1 on proinflammatory cytokine release in mononuclear cells. The releases of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from human mononuclear cells were enhanced by TSP-1 in a dose-dependent manner. Thus, the immediate and marked increase of TSP-1 expression suggests that TSP-1 has an inflammatory-associated role in MI.
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PMID:Thrombospondin-1 is induced in rat myocardial infarction and its induction is accelerated by ischemia/reperfusion. 1617 30

Diabetic nephropathy is one of the major microvascular complications in diabetes and is the leading cause of end-stage renal disease worldwide. Among various factors, angiogenesis-associated factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2 are involved in the development of diabetic nephropathy. We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model. Here, we examine the effect of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in preventing progression in the type 1 diabetic nephropathy mouse model. Endostatin peptide did not affect hyperglycemia induced by streptozotocin (STZ). Glomerular hypertrophy, hyperfiltration, and albuminuria were significantly suppressed by endostatin peptide (5 mg/kg) in STZ-induced diabetic mice. Glomerular mesangial matrix expansion, the increase of glomerular type IV collagen, endothelial area (CD31(+)), and F4/80(+) monocyte/macrophage accumulation were significantly inhibited by endostatin peptide. Increase in the renal expression of VEGF-A, flk-1, Ang-2, an antagonist of angiopoietin-1, transforming growth factor-beta1, interleukin-6, and monocyte chemoattractant protein-1 was inhibited by endostatin peptide in diabetic mice. Decrease of nephrin mRNA and protein in diabetic mice was suppressed by treatment with endostatin peptide. The level of endostatin in the renal cortex and sera was increased in diabetic mice. Endogenous renal levels of endostatin were decreased in endostatin peptide-treated groups in parallel with VEGF-A. Although serum levels of endostatin were decreased in the low-dose endostatin-peptide group, high-dose administration resulted in elevated serum levels of endostatin. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in diabetic nephropathy.
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PMID:Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. 1618 90

There are few data concerning the relationship between diabetes mellitus, the metabolic syndrome and inflammation following elective percutaneous coronary intervention (PCI). The purpose of this study was to assess basal and peak levels of candidate cytokines in 40 patients undergoing elective PCI. Patients were categorised as having diabetes mellitus, the metabolic syndrome, or neither. Patients with the metabolic syndrome exhibited significantly greater levels of tumour necrosis factor-alpha over the study period, although this was unrelated to PCI. There was a trend for increased levels of interleukin-6 following PCI, primarily among patients with metabolic syndrome. Basal levels of monocyte chemoattractant protein-1 (MCP-1) were not different among study groups; however, the metabolic syndrome cohort had a trend towards increased circulating levels of MCP-1 after PCI. In this patient population, the metabolic syndrome correlates with a heightened inflammatory response following elective PCI.
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PMID:Metabolic syndrome-mediated inflammation following elective percutaneous coronary intervention. 1630 70


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