UNIPROT:P05231 - FACTA Search

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)

Genetic factors play an important role in determining bone mass and several genes are involved in this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone mineral density (BMD) and it has been suggested recently that novel IL-6 -174 G/C allelic variants may be associated with peak BMD in young men and with bone resorption in elderly women. In this study, we assessed the relationships between IL-6 gene polymorphism, peak BMD, rate of postmenopausal BMD loss, and bone turnover in women. BMD was measured by dual-energy X-ray absorptiometry in 255 healthy premenopausal women, aged 31-57 years. BMD loss at the forearm was measured over 4 years in 298 healthy untreated postmenopausal women, 50-88 years (mean 64 years). We also measured levels of serum osteocalcin, bone alkaline phosphatase, and N-propeptide of type I collagen for bone formation and three markers of bone resorption, including urinary and serum C-terminal cross-linking telopeptide of type I collagen and urinary N-terminal telopeptide of type I collagen, in both pre- and postmenopausal women at baseline. In premenopausal women we found a significant association between IL-6 genotypes and BMD at the whole body (analysis of variance [ANOVA], p = 0.03), femoral neck (p = 0.03), trochanter (p = 0.014), Ward's triangle (p = 0.03), and total hip (p = 0.006), with subjects having the CC genotype showing 3%-7% higher BMD levels than their GG counterparts. However, after matching women with CC and GG genotypes for body height the differences decreased (2%-4%), and were no longer significant (p = 0.10-0.23). In postmenopausal women the mean rate of loss at the ultradistal radius was significantly associated with IL-6 genotypes (ANOVA, p = 0.049), with women having the CC genotype showing a significantly greater rate of bone loss (p < 0.05) compared with their GC and GG counterparts. After adjustment for weight changes, the difference in the rate of ultradistal radius bone loss between genotypes decreased and was not significant (p = 0.06 for CC vs. GG). A similar trend was observed for distal radius bone loss (p = 0.10, ANOVA), but not for the middle radius. We found no significant association between genotypes, bone turnover markers in premenopausal women, and either bone turnover or BMD in postmenopausal women. We conclude that this new functional IL-6 polymorphism was weakly associated with level of peak BMD and the rate of forearm trabecular postmenopausal bone loss in this cohort of healthy French women. IL-6 genotypes accounted only for a small proportion of the interindividual variation of both peak BMD and rate of bone loss and were not significant after adjustment for height and changes in body weight, respectively, suggesting that part of the effect may have been due to the differences in body size. Larger long-term studies are necessary to assess adequately the relationships between IL-6 genotype, rate of bone loss, and risk of fracture.
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PMID:Association between a functional interleukin-6 gene polymorphism and peak bone mineral density and postmenopausal bone loss in women: the OFELY study. 1211 Apr 11

In this study, we investigated the effect of inflammatory cytokines on matrix metalloproteinase (MMP-1) and TIMP-1 production in human dermal fibroblasts, which play a pivotal role in wound healing, ranging from the synthesis and remodeling of extracellular matrix (ECM) to the synthesis of growth factors. The balance of MMPs and TIMPs is crucial in directing successful wound repair. Human adult dermal fibroblasts were seeded in six well plates (7.5 x 10(4) cells/ml) in complete media. Eighty to ninety percent confluent cells were treated with interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) (10 ng/ml) for 6h in serum free media with suitable controls run in triplicate. Supernatants were assayed for pro-MMP-1 & TIMP-1. Extracted total RNA was used for reverse transcription polymerase chain reaction (RT-PCR) with sequence specific primers for MMP-1, TIMP-1 and beta-actin. Signal intensity was normalized to the internal control (beta-actin). Statistical analysis used ANOVA. MMP-1 and TIMP-1 mRNA expression were markedly increased with IL-6 and TNF-alpha treatment and remains unchanged with IL-1beta. Pro-MMP-1 protein levels are unchanged with TNF-alpha and significantly increased with IL-1beta and IL-6 treatment. However, TNF-alpha significantly increases TIMP-1 protein levels. Data suggests differential regulation of MMP-1 and TIMP-1 protein levels by the cytokines found in stimulated dermal fibroblasts. Further characterization of this response will provide an understanding of the mechanisms of pathogenesis of extracellular matrix (ECM) and the potential role of metalloproteinases in tissue remodeling after injury.
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PMID:Matrix metalloproteinase expression in cytokine stimulated human dermal fibroblasts. 1292 75

High circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are found in patients with hyperinsulinemia. Insulin stimulates release of IL-6 from adipocyte cultures, and it stimulates IL-6 gene expression in insulin-resistant, but not control, rat skeletal muscle. In addition, TNF-alpha may be involved in the pathogenesis of insulin resistance. Therefore, we studied the effect of insulin on IL-6 and TNF-alpha gene expression in human skeletal muscle and adipose tissue. Nine healthy young volunteers participated in the study. They underwent a 6-h hyperinsulinemic euglycemic clamp at a fixed insulin infusion rate, with blood glucose clamped at fasting level. Blood samples drawn at 0, 1, 2, 3, 4, 5, and 6 h were analyzed for IL-6 and TNF-alpha. Muscle and fat biopsies, obtained at 0, 2, 4, and 6 h, were analyzed for IL-6 and TNF-alpha mRNA with real-time PCR. IL-6 mRNA increased 11-, 3-, and 5-fold at 2, 4, and 6 h, respectively, in adipose tissue (ANOVA P = 0.027), whereas there was no significant effect of insulin on skeletal muscles. Plasma IL-6 increased during insulin stimulation. TNF-alpha mRNA increased 2.4-, 1.4-, and 2.2-fold in adipose tissue (ANOVA P = 0.001) and decreased 0.74-, 0.64-, and 0.68-fold in muscle tissue (ANOVA P = 0.04). Plasma levels of TNF-alpha were constant. In conclusion, the finding that insulin stimulates IL-6 and TNF-alpha gene expression in adipose tissue only and inhibits the TNF-alpha production in skeletal muscles suggests a differential regulation of muscle- and adipose tissue-derived IL-6 and TNF-alpha.
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PMID:Insulin stimulates interleukin-6 and tumor necrosis factor-alpha gene expression in human subcutaneous adipose tissue. 1453 68

Acute mental stress may contribute to atherosclerosis by affecting inflammation and coagulation; however, the crosstalk between inflammation and coagulation during stress has not been studied. In the present study, we investigated the association of plasma fibrinogen, plasma IL-6 (interleukin-6) and free salivary cortisol with the procoagulant marker D-dimer reflecting fibrin formation both over a 2-h period and in response to acute mental stress. Twenty-one male volunteers (mean age, 47+/-8 years) underwent the Trier Social Stress Test combining a 3-min preparation phase, a 5-min job interview and 5-min mental arithmetic test before an audience. IL-6, fibrinogen, D-dimer and cortisol were measured immediately before and after stress, and after 45 min and 105 min of recovery from stress. Two distinct areas under the curve were computed to obtain integrated measures of total protein activity over the entire 2-h period and of stress reactivity of proteins. IL-6 (P < 0.001), fibrinogen (P = 0.001), D-dimer (P = 0.021) and cortisol (P < 0.001) had all significantly changed across the four time points assessed, as determined by ANOVA. For the entire 2-h period, total fibrinogen activity (R2 = 0.33, P = 0.007) and total cortisol activity (DeltaR2 = 0.17, P = 0.034) explained 50% of the variance in total D-dimer activity. Stress-induced changes in fibrinogen (R2 = 0.47, P = 0.001) and IL-6 (DeltaR2 = 0.18, P = 0.008) together explained 65% of the variance in D-dimer reactivity to stress. Total fibrin formation was independently predicted by fibrinogen and hypothalamo-pituitary-adrenal activity. Pro-inflammatory and procoagulant changes with stress were associated. Aside from fibrinogen reactivity, IL-6 reactivity was an independent predictor of stress-induced fibrin formation.
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PMID:Different contribution of interleukin-6 and cortisol activity to total plasma fibrin concentration and to acute mental stress-induced fibrin formation. 1575 67

The major focus of intrahepatic arterial (IHA) administration of adenoviruses (Ad) has been on safety. Currently, there is little published data on the biological responses to Ad when administered via this route. As part of a Phase I study, we evaluated biological responses to a replication-defective adenovirus encoding the p53 transgene (SCH 58500) when administered by hepatic arterial infusion to patients with primarily colorectal cancer metastatic to the liver. In analyzing biological responses to the Ad vector, we found that both total and neutralizing Ad antibodies increased weeks after SCH 58500 infusion. The fold increase in antibody titers was not dependent on SCH 58500 dosage. The proinflammatory cytokine interleukin-6 (IL-6) transiently peaked within 6 h of dosing. The cytokine sTNF-R2 showed elevation by 24 h post-treatment, and fold increases were directly related to SCH 58500 doses. Cytokines TNF-alpha, IL-1beta, and sTNF-R1 showed no increased levels over 24 h. Predose antibody levels did not appear to predict transduction, nor did serum Ad neutralizing factor (SNF). Delivery of SCH 58500 to tumor tissue occurred, though we found distribution more predominantly in liver tissues, as opposed to tumors. RT-PCR showed significantly higher expression levels (P<0.0001, ANOVA) for adenovirus type 2 and 5 receptor (CAR) in liver tissues, suggesting a correlation with transduction. Evidence of tumor-specific apoptotic activity was provided by laser scanning cytometry, which determined a coincidence of elevated nuclear p53 protein expression with apoptosis in patient tissue. IHA administration of a replication defective adenovirus is a feasible mode of delivery, allowing for exogenous transfer of the p53 gene into target tissues, with evidence of functional p53. Limited and transient inflammatory responses to the drug occurred, but pre-existing immunity to Ad did not preclude SCH 58500 delivery.
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PMID:Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial. 1608 81

We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])-induced cytokine production. This was a randomized, double-blind, placebo-controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to 200% and 500% before infusion of 2 ng/kg endotoxin (LPS). Infusion of antithrombin dose-dependently decreased coagulation (P < .01 by repeated-measures ANOVA): peak levels of prothrombin fragment (1.8 nmol/L [95% confidence interval (CI), 1.3-2.3 nmol/L] in the 500% antithrombin group and 4.4 nmol/L [95% CI, 2.7-6.2 nmol/L] in the placebo group at 4 hours), thrombin antithrombin complexes (12 microg/L [95% CI, 8-16 microg/L] in the 500% antithrombin group and 34 microg/L [95% CI, 20-48 microg/L] in the placebo group at 4 hours), and D-dimer (0.2 microg/L [95% CI, 0.1-0.2 microg/L] in the 500% antithrombin group and 0.5 microg/L [95% CI, 0.4-0.7 microg/L] in the placebo group). Recombinant human antithrombin decreased peak interleukin-6 levels by 40% (222 pg/mL [95% CI, 148-295 pg/mL] and 216 pg/mL [95% CI, 112-320 pg/mL] in the 500% and 200% antithrombin groups, respectively, versus 357 pg/mL [95% CI, 241-474 pg/mL] in the placebo group; P < .001 by ANOVA). Finally, infusion of recombinant human antithrombin rapidly and transiently decreased neutrophil counts (by 19% [95% CI, 8%-30%] in the 500% antithrombin group versus 6% [95% CI, 1%-10%] in the placebo group, P = .002 by Kruskal-Wallis ANOVA) and monocyte counts (by 30% [95% CI, 16%-44%] in the 500% antithrombin group and 18% [95% CI, 9%-28%] in the 200% antithrombin group versus 8% [95% CI, 5%-20%] in the placebo group, P = .04) before LPS challenge, indicating that recombinant human antithrombin directly interacts with these leukocyte subsets. In summary, recombinant human antithrombin dose-dependently inhibited tissue factor-triggered coagulation. Effects on leukocytes and inhibition of interleukin-6 release seem to represent specific pharmacodynamic properties of recombinant human antithrombin.
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PMID:Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia. 1641 39

Elevated plasma concentration of C-reactive protein has emerged as an important predictor of future cardiovascular diseases and metabolic abnormalities in apparently healthy individuals. Obese individuals tend to have elevated C-reactive protein concentrations. Weight loss induces a change in this protein, and single nucleotide polymorphisms in regulating genes might affect this change, since C-reactive protein concentration is known to be approximately 40-50% heritable. Our aim was to study the association between the IL6 -174(G/C), IL1B +3,954(C/T) and CRP +1,059(G/C) single nucleotide polymorphisms, and CRP concentrations in obese men during a weight reduction program. We genotyped 72 obese men who had participated in a weight reduction program. Their C-reactive protein concentrations, interleukin-6 levels and fat mass were determined at two time points: at baseline and after weight reduction (after 2 months). After weight reduction, the mean weight loss was 14.3 kg. Median C-reactive protein concentrations decreased, after weight reduction, from 1.72 to 1.22 mg/l (p < 0.02). The baseline C-reactive protein concentration did not differ between the IL6-174(G/C) genotypes, but after weight loss, concentrations differed (p = 0.03 Kruskal-Wallis test); the highest concentration was found in the CC genotype (CC 1.01 versus GG 1.93 mg/l, p = 0.007 ANOVA post-hoc test). This change in concentration was associated with the IL6-174(G/C) genotype (p = 0.01, Kruskal-Wallis test), being least in the CC genotype. The other single nucleotide polymorphisms studied were not associated with CRP concentrations. Our results show that, at baseline, there is no difference in C-reactive protein concentrations among the different IL6-174(G/C) genotypes, but after weight loss the CC genotype is associated with highest C-reactive protein concentrations, resulting from the fact that C-reactive protein seems not to decrease with weight loss in this genotype.
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PMID:Association of the IL6-174(G/C) polymorphism with C-reactive protein concentration after weight loss in obese men. 1684 32

Inflammatory cytokines are released in response to stress, tissue damage, and infection. Acutely, this response is adaptive; however, chronic elevation of inflammatory proteins can contribute to health problems including cardiovascular, endocrine, mood, and sleep disorders. Few studies have examined how sleep deprivation acutely affects inflammatory markers, which was the aim of the current study. Nineteen healthy men and women aged 28.05+/-8.56 (mean+/-SD) were totally sleep deprived for 40 h under constant routine conditions. Pro-inflammatory markers: intracellular adhesion molecule-1 (ICAM-1), E-selectin, vascular adhesion molecule-1 (VCAM-1), c-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), and the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) were assayed in plasma. Daytime levels during baseline (hours 1-15 of scheduled wakefulness) were compared to daytime levels during sleep deprivation (hours 25-39 of scheduled wakefulness), thus controlling for circadian phase within an individual. Repeated measures ANOVA with planned comparisons showed that 40 h of total sleep deprivation induced a significant increase in E-selectin, ICAM-1, IL-1beta, and IL-1ra, a significant decrease in CRP and IL-6, and no significant change in VCAM-1. Alterations in circulating levels of pro- and anti-inflammatory cytokines and cell adhesion molecules during sleep deprivation were consistent with both increased and decreased inflammation. These findings suggest that one night of sleep loss triggers a stress response that includes stimulation of both pro- and anti-inflammatory proteins in the healthy young subjects tested under our experimental conditions.
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PMID:The effects of 40 hours of total sleep deprivation on inflammatory markers in healthy young adults. 1752 14

Inhalation of CO2 or isoflurane is a commonly used method of euthanasia with mice, but information related to their effects on serum inflammatory markers in chronic models of inflammation is limited. In the current study, nineteen-week old DBA female mice with (n = 53) or without (n = 51) collagen-induced arthritis were randomly assigned to euthanization with CO2 (n = 55) or isoflurane (n = 49. Plasma was collected for the measurement of soluble intercellular adhesion molecule-1 (sICAM-1), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) by ELISA. When mice without and with collagen-induced arthritis were pooled, compared to CO2, administration of isoflurane was associated with lower production of the pro-inflammatory cytokines TNF-alpha (pg/ml, mean +/- SEM) (26.1 +/- 2.82 versus 48.1 +/- 7.99) and IL-6 (25.18 +/- 2.73 versus 48.1 +/- 6.82) (ANOVA, p < 0.05). In contrast to TNF-alpha and IL-6, administration of CO2 decreased the plasma sICAM-1 level (1170+/- 50 versus 758 +/- 24 for CO2) (p < 0.00001). When data were analyzed as a function of collagen-induced arthritis, the differences between CO2 and isoflurane persisted. Low plasma sICAM-1 levels found in CO2 euthanasia group may be due to degradation. Since mice are the most common animal model for studying inflammation, researchers should be aware of these iatrogenic experimental variables before interpreting their data.
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PMID:Differential effects of isoflurane and CO2 inhalation on plasma levels of inflammatory markers associated with collagen-induced arthritis in DBA mice. 1934 22

Mycobacterium tuberculosis (MTB) is a slow growing bacterium. Therefore, the immune responses associated with resolution of infection or development of disease post-exposure may take several months to evolve. We have carried out a prospective longitudinal study in a high TB transmission setting to determine the evolution of biomarkers in a recently exposed household contact (HC = 77) and their respective sputum positive index cases (TB = 17). Mycobacterium-induced cytokines [interferon-gamma (IFN-gamma), tumour necrosis factor-alpha, interleukin-6 (IL-6) and IL-10)] were assessed in whole blood cultures and immunoglobulin G (IgG1) antibodies in plasma. When compared with non-exposed community controls (endemic controls = 59) the HC group at intake showed changes in biomarkers commensurate with recent exposure. The HC group showed significant increases in IFN-gamma between 0 and 6 months (paired t-test; P = 0.001) and IL-0 between 6 and 12 months (P = 0.001), most likely reflecting the role of these cytokines in resolution and immune recovery from infection as this HC cohort remained symptom-free for 4 years without prophylactic treatment. When the TB group post-treatment was compared with the HC group, the best discriminators (ANOVA; repeated measures) were IL-10 responses at 0 (P = 0.004) and 6 months (P = 0.001) and IgG1 at 6 (P = 0.004) and 12 months (P = 0.014) with a 3-4 fold higher responses in the TB group. Therefore, within each group, biomarkers show unique profile of responses. These studies highlighted the importance of assessing multiple biomarkers in longitudinal studies for providing better understanding of protective biomarker profiles associated with resolution of clinical and subclinical infections in TB.
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PMID:Dynamic changes in biomarker profiles associated with clinical and subclinical tuberculosis in a high transmission setting: a four-year follow-up study. 1943 15

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