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)

Enterohemorrhagic Escherichia coli (EHEC) induces hemorrhagic colitis and hemolytic uremic syndrome (HUS). Morbidity and mortality are increased in HUS patients with neurologic complications. To determine the pathogenesis of the central nervous system (CNS) involvement in HUS by EHEC, we determined the serum concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1), IL-10, interferon-gamma (IFN-gamma), IL-2, IL-4, soluble E-selectin (sE-selectin), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) during the acute stage in children with HUS with or without CNS involvement. Serum concentrations of IL-6, IL-10, sTNFR1, sE-selectin, MMP-9, and TIMP-1, but not TNF-alpha, IFN-gamma, IL-2, or IL-4, were significantly higher in patients with HUS with encephalopathy compared with controls. Serum IL-6, sTNFR1 and TIMP-1 concentrations were significantly higher in patients with HUS with encephalopathy compared with those with HUS without encephalopathy (P=0.031, P=0.005, and P=0.007, respectively) and those with acute colitis without HUS (P=0.011, P<0.001, and P=0.005, respectively). There were no significant differences in hemoglobin, platelet counts, leukocyte counts, or serum concentrations of IL-10, sE-selectin, MMP-9, aspartate aminotransferase, lactate dehydrogenase, blood urea nitrogen, creatinine, or C-reactive protein between the HUS patients with and without encephalopathy. Our preliminary study suggests that serum IL-6, sTNFR1 and TIMP-1 levels, particularly sTNFR1 and TIMP-1, are important for predicting neurological complications in patients with HUS.
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PMID:Soluble tumor necrosis factor receptor 1 and tissue inhibitor of metalloproteinase-1 in hemolytic uremic syndrome with encephalopathy. 1841 Sep 71

Inflammation, an independent cardiovascular disease risk factor is common in patients with chronic kidney disease. Suppressors of cytokine signaling (SOCS) are induced by cytokines in a variety of cells and modulate inflammatory responses. We hypothesized that in chronic kidney disease, SOCS expression in peripheral blood mononuclear cells is increased, and related to inflammation and renal function. We also tested correlations between SOCS expression and biomarkers and risk factors of cardiovascular disease. Whether monocytes and lymphocytes differentially respond to interleukin-6 (IL-6) was tested ex vivo. Monocytes and lymphocytes were isolated from peripheral blood of chronic kidney disease patients (n=9) and controls (n=11). In three other healthy subjects, whole blood was incubated with IL-6 before cell isolation. SOCS expression was assessed by real-time quantitative PCR. Plasma cytokines were measured as well as pulse wave velocity. SOCS3 expression was increased in monocytes and SOCS1 in lymphocytes along with increased plasma levels of IL-6 and tumor necrosis factor-alpha (TNFalpha) in chronic kidney disease patients. While monocyte SOCS3 correlated with glomerular filtration rate, urea and diastolic blood pressure, lymphocyte SOCS1 correlated with TNFalpha, pulse wave velocity and systolic blood pressure. IL-6 stimulation of whole blood caused expression of different SOCS genes in monocytes and lymphocytes. Increased expression of SOCS3 in monocytes versus SOCS1 in lymphocytes coincided with elevated plasma levels of IL-6 and TNFalpha, suggesting that these cell types process the uremic milieu differently. This could reflect cell-specific responses to inflammation, as supported by our ex vivo study. Moreover, increased SOCS expression in peripheral blood mononuclear cells correlated with decreased renal function. Since chronic kidney disease predisposes to cardiovascular disease, we speculate that increased SOCS expression in peripheral blood mononuclear cells could be a new marker of cardiovascular disease in chronic kidney disease patients.
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PMID:Increased expression of SOCS3 in monocytes and SOCS1 in lymphocytes correlates with progressive loss of renal function and cardiovascular risk factors in chronic kidney disease. 1865 67

Suramin is a symmetric polysulfonated naphthylamine-benzamide urea derivative approved for the treatment of trypanosomiasis and onchocerciasis and a known P2 (ATP/UTP purine receptor) antagonist. Here, we report its ability to inhibit the important CD40-CD154 costi-mulatory interaction required for T cell activation and the development of an effective immune response. In vitro, it inhibited the binding of both human and murine CD154 (CD40L) to their receptor (CD40) even in the presence of protein-containing media and prevented the CD154-induced proliferation of human B cells as well as the corresponding increase in surface expression of CD86, CD80, CD40, and MHC class II in a concentration-dependent manner. Furthermore, in isolated human islets, it also decreased the CD154-induced release of inflammatory cytokines such as IFN-g, interleukin-6 (IL-6), and IL-8. Suramin was selected for investigation because it has been reported to be an inhibitor of the interaction of TNF-a with its receptor and CD154 is a member of the TNF-family. However, it turned out to be a considerably, about 30-fold, more effective inhibitor of the CD40-CD154 protein-protein interaction than of the corresponding TNF interaction. Its median inhibitory concentration (IC50 50 mM) is somewhat higher than for the P2-receptor, but well within the range of its therapeutic concentration levels. Suramin shows considerable polypharmacology, but its interference with the positive costimulatory interaction might provide a possible, not yet identified mechanism for its ability to suppress T cell activity and induce immunosuppression, which might also have limited its clinical usefulness in the treatment of AIDS and cancer.
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PMID:Suramin inhibits the CD40-CD154 costimulatory interaction: a possible mechanism for immunosuppressive effects. 1928 94

Expression of the p16(INK4a) tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age-induced functional decline of certain self-renewing compartments. These observations have suggested that p16(INK4a) expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16(INK4a) expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T-lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationship with donor characteristics. Expression of p16(INK4a), but not other INK4/ARF transcripts, appeared to exponentially increase with donor chronologic age. Importantly, p16(INK4a) expression did not independently correlate with gender or body-mass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16(INK4a) expression was associated with plasma interleukin-6 concentration, a marker of human frailty. These data suggest that p16(INK4a) expression in PBTL is an easily measured, peripheral blood biomarker of molecular age.
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PMID:Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging. 1948 66

Membranous glomerulonephritis (MGN) remains the most common cause of adult-onset nephrotic syndrome in the world and up to 40% of untreated patients will progress to end-stage renal disease. Although the treatment of MGN with immunosuppressants or steroid hormones can attenuate the deterioration of renal function, numerous treatment-related complications have also been established. In this study, the ameliorative effects of arctiin, a natural compound isolated from the fruits of Arctium lappa, on rat glomerulonephritis induced by cationic bovine serum albumin (cBSA) were determined. After oral administration of arctiin (30, 60, 120 mg/kgd) for three weeks, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) and 24-h urine protein content markedly decreased, while endogenous creatinine clearance rate (ECcr) significantly increased. The parameters of renal lesion, hypercellularity, infiltration of polymorphonuclear leukocyte (PMN), fibrinoid necrosis, focal and segmental proliferation and interstitial infiltration, were reversed. In addition, we observed that arctiin evidently reduced the levels of malondialdehyde (MDA) and pro-inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha), suppressed nuclear factor-kappaB p65 (NF-kappaB) DNA binding activity, and enhanced superoxide dismutase (SOD) activity. These findings suggest that the ameliorative effects of arctiin on glomerulonephritis is carried out mainly by suppression of NF-kappaB activation and nuclear translocation and the decreases in the levels of these pro-inflammatory cytokines, while SOD is involved in the inhibitory pathway of NF-kappaB activation. Arctiin has favorable potency for the development of an inhibitory agent of NF-kappaB and further application to clinical treatment of glomerulonephritis, though clinical studies are required.
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PMID:Ameliorative effects of arctiin from Arctium lappa on experimental glomerulonephritis in rats. 1952 15

Despite data that traditional laboratory-based outcome measures in dialysis are improving over time, population-based data indicate that mortality rates are not improving in parallel. With increased focus on performance measures based on laboratory-based outcomes (e.g., hematocrit, albumin, and parathyroid hormone), less emphasis has been placed on other markers, some of which may be stronger predictors of mortality. We performed a systematic review to interpret the predictive value of laboratory-based outcome measures in dialysis. We identified studies with data regarding the predictive value of laboratory-based outcomes for mortality in dialysis. We calculated the sample size-weighted pooled relative risk of death with dichotomized "high" vs. "low" levels of each measure. We rank-ordered predictors by scaling the pooled relative risk of each measure by its pooled standard deviation. There were 5171 titles, of which 128 (representing 44 laboratory-based outcomes) were selected. Nine were significantly associated with mortality, in order of decreasing scaled effect size: (1) tumor necrosis factor-alpha, (2) hematocrit, (3) interleukin-6, (4) troponin T, (5) Kt/V(urea), (6) prealbumin, (7) urea reduction ratio, (8) serum albumin, and (9) C-reactive protein. Other oft-cited measures such as calcium phosphate product and parathyroid hormone were not significantly associated with mortality in pooled analysis. Quality improvement efforts to improve traditional laboratory-based outcomes in end-stage renal disease are necessary, but likely insufficient, to improve overall mortality in dialysis. Renewed consideration of cardiovascular, inflammatory, and nutritional markers that are especially strong predictors of mortality may have important implications for risk stratification and targeted therapeutic interventions.
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PMID:The relationship between laboratory-based outcome measures and mortality in end-stage renal disease: a systematic review. 1958 4

One of the greatest challenges in the attempt to create functional bioartificial liver designs is the maintenance of porcine hepatocyte differentiated functions in vitro. Co-cultivation of hepatocytes with nonparenchymal cells may be beneficial for optimizing cell functions via mimicry of physiological microenvironment. However, the underlying mechanisms remain to be elucidated. An equal number of freshly isolated porcine hepatocytes and purified bone marrow mesenchymal stem cells (MSCS) was randomly co-cultured and the morphological and functional changes of heterotypic interactions were characterized. Furthermore, contributions of soluble factors involved in the separated co-culture system were evaluated. The purity of the third-passage MSCS and primary hepatocytes was more than 90% and 99%, respectively. Hepatocyte viability was greater than 95%. A rapid attachment and self-organization of three-dimensional hepatocyte spheroids were encouraged, which was due to the supporting MSCS of high motility. The elevated induction of both albumin production and urea synthesis was achieved in co-culture (P < 0.05). Data from semipermeable membrane cultures suggested that interleukin-6 is one of the key stimulators in hepatic functional enhancement. These results demonstrate for the first time that soluble factors have beneficial effects on the preservation of hepatic morphology and functionality in the co-culture of hepatocytes with MSCS in vitro, which could represent a promising tool for tissue engineering, cell biology, and bioartificial liver devices.
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PMID:Contribution of bone marrow mesenchymal stem cells to porcine hepatocyte culture in vitro. 1976 23

In this study, the effects of fucoidan on aspirin-induced ulcers in rats were evaluated: both biochemical and immunological parameters were taken into consideration. The status of stomach tissue glycogen storage and histological changes were also examined. Examination of basic biochemical parameters showed significant (p<0.01) alterations in aspartate (AST) and alanine (ALT) transaminases in ulcer-induced rats. Also, moderate alterations (p<0.05) were observed in the levels of cholesterol and blood urea nitrogen (BUN). Histopathological examination showed neutrophil infiltration and inflammation in oxyntic cells with altered glycogen storage. Analysis of serum cytokines of aspirin-induced rats showed a moderate decrease in interleukin-10 (IL-10) with considerable increase of interleukin-6 (IL-6) and interferon-gamma (INF-gamma) when compared with control. Administration of fucoidan showed considerable (p<0.05) protection against ulceration by inhibiting the acute alterations of AST, ALT, cytokines and stomach glycogen. However, aggravated serum INF-gamma was observed in the fucoidan-pretreated group. These findings suggest that the anti-ulcer property of fucoidan might contribute in protecting the inflammatory cytokine-mediated oxidative damage to gastric mucosa.
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PMID:Effect of fucoidan on aspirin-induced stomach ulceration in rats. 1978 92

Cisplatin (CDDP), a major chemotherapeutic agent used to treat solid tumors, is known to induce acute renal failure (ARF). The progression of tissue injury involves the coordination of inflammatory and repair responses. Interleukin-6 (IL-6) has been suggested to modulate inflammatory and repair processes in various tissue injuries. In this study, we analyzed IL-6 regulation during CDDP-induced ARF in wild-type (WT) mice and determined the pathological role of IL-6 using IL-6 knockout ((-/-)) mice. A correlation between increase in serum IL-6 level and blood urea nitrogen level was found in WT mice. Renal IL-6 expression in most proximal tubular cells and suppressor of cytokine signaling 3 (SOCS3) gene expression significantly increased in WT mice after administration of CDDP, suggesting active IL-6 signaling during CDDP-induced ARF development. Interestingly, renal dysfunction occurred soon after administration of CDDP and became more severe in IL-6(-/-) mice than that in WT mice. In contrast, the survival rate of IL-6(-/-) mice (50% at 8 days) was better than that of WT mice (10%). Induction levels of proapoptotic Bcl-2 associated X protein (Bax) in renal proximal tubular cells was significantly higher in IL-6(-/-) mice than in WT mice at 24h after CDDP injection. Levels of antiapoptotic proteins, Bcl-2 and Bcl-extra large (Bcl-x(L)), in IL-6(-/-) groups were significantly higher than those in CDDP-treated WT groups throughout the experimental period. Bax might contribute to the development of CDDP-induced ARF at 24h; however, high expression levels of Bcl-x(L) and Bcl-2 might overcome the proapoptosis signaling at 72 h in IL-6(-/-) mice. These results indicated that local and systemic elevation of IL-6 contributes to the development of CDDP-induced ARF and that IL-6 produced in renal tubular cells prevents progression of ARF at the early stage. IL-6 deficiency accelerates CDDP-induced ARF but not development of systemic injury.
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PMID:Interleukin-6 deficiency accelerates cisplatin-induced acute renal failure but not systemic injury. 1983 67

Sodium arsenite (NaAs)-induced autophagic cell death (ACD) of a mouse renal tubular epithelial cell line (mProx24), which expresses enhanced levels of interleukin-6 (IL-6), was reduced by the suppression of autophagy by 3-methyladenine or Atg7 knockdown. The inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) signal pathway by anti-IL-6 antibody or a Jak2 inhibitor (AG490) exaggerated ACD of mProx24 cells after NaAs challenge, attenuating STAT3 activation and reciprocally enhancing extracellular signal-regulated kinase (ERK) phosphorylation. In contrast, an ERK inhibitor, PD98059, reduced NaAs-induced ACD in mProx24 cells. Subcutaneous injection of NaAs (12.5 mg/kg) into BALB/c (wild-type) mice enhanced intrarenal expression of IL-6, mainly produced by tubular cells, and caused severe renal injury characterized by hemorrhages, acute tubular necrosis, cast formation, and brush border disappearance, with increases in serum urea nitrogen (blood urea nitrogen) and creatinine levels. In addition, IL-6-deficient (IL-6(-/-)) mice exhibited exaggerated histopathological changes with higher blood urea nitrogen and creatinine levels. Moreover, in IL-6(-/-) mice treated with NaAs, ACD in renal tubular cells was significantly augmented, along with diminished STAT3 activation and reciprocal enhancement of ERK signaling, compared with wild-type mice. Finally, the administration of exogenous IL-6 into wild-type mice significantly reduced NaAs-induced ACD along with diminished ERK activation and eventually alleviated acute renal dysfunction. Thus, IL-6/STAT3 signal pathway could inhibit ERK activation, a crucial step for ACD, eventually attenuating NaAs-induced renal dysfunction.
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PMID:The absence of interleukin-6 enhanced arsenite-induced renal injury by promoting autophagy of tubular epithelial cells with aberrant extracellular signal-regulated kinase activation. 2000 37


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