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)

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.
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PMID:Blockade of tissue factor: treatment for organ injury in established sepsis. 1271 43

Aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the type I tumor necrosis factor receptor (TNFR1) and promotes receptor shedding. Because hydroxamic acid-based metalloprotease inhibitors prevent shedding of both TNFR1 and the interleukin-6 receptor (IL-6Ralpha), we hypothesized that ARTS-1 might also regulate shedding of IL-6Ralpha, a member of the type I cytokine receptor superfamily that is structurally different from TNFR1. Reciprocal co-immunoprecipitation experiments identified that membrane-associated ARTS-1 directly binds to a 55-kDa IL-6Ralpha, a size consistent with soluble IL-6Ralpha generated by ectodomain cleavage of the membrane-bound receptor. Furthermore, ARTS-1 promoted IL-6Ralpha shedding, as demonstrated by a direct correlation between increased membrane-associated ARTS-1 protein, increased IL-6Ralpha shedding, and decreased membrane-associated IL-6Ralpha in cell lines overexpressing ARTS-1. The absence of basal IL-6Ralpha shedding from arts-1 knock-out cells identified that ARTS-1 was required for constitutive IL-6Ralpha shedding. Furthermore, the mechanism of constitutive IL-6Ralpha shedding requires ARTS-1 catalytic activity. Thus, ARTS-1 promotes the shedding of two cytokine receptor superfamilies, the type I cytokine receptor superfamily (IL-6Ralpha) and the TNF receptor superfamily (TNFR1). We propose that ARTS-1 is a multifunctional aminopeptidase that may modulate inflammatory events by promoting IL-6Ralpha and TNFR1 shedding.
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PMID:An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding. 1274 71

The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a FADD-like interferon converting enzyme or caspase 8 (FLICE) inhibitory protein (vFLIP) that prevents death receptor-mediated apoptosis by inhibiting the recruitment and activation of FLICE. Since vFLIP physically interacts with tumor necrosis factor receptor associated factor 2 (TRAF2) and TRAF2 mediates activation of the jun NH(2)-terminal kinase (JNK)/activation protein 1 (AP1) pathway, we hypothesized that vFLIP might also activate this pathway. To evaluate this hypothesis, we transiently and stably transfected a vFLIP expression construct and performed several complementary assays to document that vFLIP activates the JNK/AP1 pathway and does so in a TRAF-dependent fashion. As vFLIP also activates the nuclear factor kappaB (NF-kappaB) signaling pathway and the NF-kappaB and JNK/AP1 pathways both modulate cellular interleukin-6 (cIL-6) expression, we postulated that vFLIP induces expression of this cytokine. We show that vFLIP induces cIL-6 expression and activates the cIL-6 promoter, and maximal activation of the cIL-6 promoter by vFLIP requires NF-kappaB and AP1 activation. In addition, vFLIP and latency-associated nuclear antigen (LANA), another KSHV-encoded latent protein, potentiate each other's ability to activate the cIL-6 promoter. Gene silencing experiments by RNA interference demonstrate that vFLIP in BCBL-1 endogenously infected primary effusion lymphoma (PEL) cells mediates JNK/AP1 activation and cIL-6 expression. Thus, we conclude that vFLIP, in addition to its known effects on NF-kappaB activation, also modulates the JNK/AP1 pathway and induces gene expression from the cIL-6 promoter in a JNK/AP1-dependent fashion.
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PMID:Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-kappaB and JNK/AP1 pathways. 1277 88

The clinical features, the underlying CIAS1 mutation, and the results of cytokine analyses are described for a 10-year-old German boy with neonatal-onset multisystem inflammatory disease, whose condition improved with age. Disease onset occurred at 26 months of age with predominantly cutaneous (urticarial rash) and neurologic (headache, chronic meningitis) symptoms including early bilateral optic nerve atrophy, whereas articular manifestations were mild. Sequence analysis of exon 3 of the CIAS1 gene revealed heterozygosity for a novel missense mutation. A T515C transition led to the replacement of isoleucine by threonine at amino acid position 172 (I172T) in a region of cryopyrin flanking the PYRIN and NACHT domains. This mutation was not present in the parents or in 11 controls and therefore was considered to be a de novo mutation. Enzyme-linked immunosorbent assays were performed to determine interleukin-6 and soluble tumor necrosis factor receptor superfamily 1B levels in the patient's serum and cerebrospinal fluid (CSF). Concentrations were highly elevated in the CSF, whereas corresponding serum levels remained low. The strong cytokine activation in the CSF corresponded with the neurologic symptoms. Local activation of intrathecal macrophages may therefore be an important pathogenetic mechanism. CSF cytokine levels decreased to normal under corticosteroid and intrathecal methotrexate therapy. When the boy reached the age of 5.5 years, treatment was stopped, and he has remained relapse-free.
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PMID:A novel CIAS1 mutation and plasma/cerebrospinal fluid cytokine profile in a German patient with neonatal-onset multisystem inflammatory disease responsive to methotrexate therapy. 1523 84

Short 21-mer double-stranded/small-interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia. The ds/siRNAs were transfected into bcr-abl-positive K-562 (derived from blast crisis chronic myelogenous leukemia), using lipofectamine. Penetrating of ds/siRNAs into the cells was detected by fluorescent confocal microscopy, using fluorescein-labeled ds/siRNAs. The cells were treated with mix of three siRNA sequences (3 x 60 nM) during 6 days with three repetitive transfections. The siRNA-treatment was accompanied with significant reduction of bcr-abl mRNA, p210, protein tyrosine kinase activity and cell proliferation index. Treatment of cells with Glivec (during 8 days with four repetitive doses, 180 nM single dose) resulted in analogous reduction of cell proliferation activity, stronger suppression of protein tyrosine kinase activity, and very low reduction of p210. siRNA-mix and Glivec did not affect significantly the viability of normal lymphocytes. Microarray analysis of siRNA- and Glivec-treated K-562 cells demonstrated that both pathways of bcr-abl suppression were accompanied with overexpression and suppression of many different oncogenes, apoptotic/antiapoptotic and cell proliferation factors. The following genes of interest were found to decrease in relatively equal degree in both siRNA- and Glivec-treated cells: Bcd orf1 and orf2 proto-oncogene, chromatin-specific transcription elongation factor FACT 140-kDa subunit mRNA, gene encoding splicing factor SF1, and mRNA for Tec protein tyrosine kinase. siRNA-mix and Glivec provoked overexpression of the following common genes: c-jun proto-oncogene, protein kinase C-alpha, pvt-1 oncogene homologue (myc activator), interleukin-6, 1-8D gene from interferon-inducible gene family, tumor necrosis factor receptor superfamily (10b), and STAT-induced STAT inhibitor.
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PMID:Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec alters different oncogenes, apoptotic/antiapoptotic genes and cell proliferation factors (microarray study). 1525 64

Recent evidence suggests that CD38, an ectoenzyme that converts NAD(+) to cyclic ADP-ribose (cADPr), may play a role in cytokine-induced airway smooth muscle (ASM) cell hyper-responsiveness, a key feature associated with chronic asthma. In the present study, we investigated the major signaling pathways by which tumor necrosis factor-alpha (TNFalpha) induces CD38 expression and its role in regulating gene expression in human ASM cells. Using flow cytometry analyses, TNFalpha enhanced CD38 expression in a manner that was time-(0-24 h), concentration-(0.1-40 ng/ml), and protein synthesis-(cycloheximide blockade) dependent. A selective agonistic antibody against tumor necrosis factor receptor (TNFR) 1 also augmented CD38 expression, whereas anti-TNFR2 antagonistic antibody did not prevent the TNFalpha response. Inhibition of the Janus activated kinase/signal transducer and activator of transcription pathways using the soluble inhibitor 2-(1,1-dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz-[h]imidaz[4,5-f]isoquinolin-7-one (DBI) or with neutralizing antibody against interferon beta (IFNbeta) completely abrogated TNFalpha-induced CD38 expression at both protein and mRNA levels. Combining TNFalpha (0.1 and 1 ng/ml) and IFNbeta (100 IU/ml) at concentrations alone that had little effect on CD38 expression induced a robust synergistic induction of CD38 mRNA and protein levels. 8-Bromo-cADPr, a cADPr antagonist, significantly augmented TNFalpha-induced interleukin-6 secretion, whereas regulated on activation normal T cell expressed and secreted secretion was suppressed. 8-Bromo-cADPr, however, did not affect TNFalpha-induced cell surface expression of intercellular adhesion molecule-1. Our study is the first to demonstrate that IFNbeta-dependent activation of CD38 pathway is a novel component by which TNFalpha differentially regulates the expression of inflammatory genes in ASM cells.
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PMID:Tumor necrosis factor-alpha differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-beta-dependent CD38 pathway. 1526 23

The stromal compartments of hematopoietic organs (eg, spleen) are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend murine leukemia virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared with age-matched sham controls. In vitro, the proliferation of primary erythroleukemic cells cocultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in cocultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), macrophage chemoattractant protein-5 (MCP-5), soluble tumor necrosis factor receptor-1 (sTNFR1), IL-12p70, tumor necrosis factor-alpha (TNF-alpha), and IL-2 over normal splenocytes. Medium supplemented with both VEGF-A and MCP-5 could sustain proliferation of primary erythroleukemic cells in vitro, and significant proliferative suppression was observed upon addition of neutralizing antibodies to either of these factors. Furthermore, in vivo administration of a neutralizing antibody to VEGF-A extended survival times of erythroleukemic mice in comparison with controls. These findings suggest that VEGF-A and MCP-5 are potentially pivotal paracrine mediators occurring within the diseased splenic microenvironment capable of promoting disease acceleration and expansion of erythroleukemic blasts.
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PMID:The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells. 1570 19

We have established an animal model of coronary arteritis which is histopathologically similar to that observed in cases of Kawasaki disease (KD), is a well-known childhood vasculitis syndrome. Coronary arteritis in this mouse model has been induced by intraperitoneal injection of Candida albicans -derived substances (CADS). Arteritis varied by mouse strain with the highest incidence by 71.1% (27/38) found in C3H/HeN mice, but absent in CBA/JN mice (0%, 0/27), suggesting association of genomic background to develop the disease. The present study aims to elucidate the susceptibility loci associated with coronary arteritis by using this animal model. The association of the onset of arteritis with polymorphic microsatellite markers between the two strains was examined using one hundred and fifteen of N1 backcross progeny [(CBAxC3H)F1xC3H]. Based on our analysis, arteritis-susceptibility loci with suggestive linkage were mapped on D1Mit171 and D1Mit245(map position 20.2 cM) on chromosome 1 (P=0.0019). These loci include several kinds of inflammatory cytokine receptors, such as interleukin 1 receptor and tumor necrosis factor receptor. We also found the cytokine response against CADS, levels of inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6 in sera increased within 24 hr after CADS injection. Our results may indicate based on genomics that ligand-receptor interaction between these inflammatory cytokines and the receptors of these cytokines may affect the onset of arteritis.
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PMID:Susceptibility loci to coronary arteritis in animal model of Kawasaki disease induced with Candida albicans -derived substances. 1572 3

In observational studies, statins are associated with lower mortality in patients with heart failure (HF), including those with nonischemic HF. Such benefits could be related to anti-inflammatory effects; however, the effects of statins on systemic inflammation in HF are not well-established. We conducted a 16-week, single-center, randomized, double-blind, placebo-controlled, crossover clinical trial of the effects of atorvastatin 10 mg/day on concentrations of systemic inflammatory markers in 22 patients with HF (including 20 with nonischemic HF) with New York Heart Association class II or III symptoms and left ventricular ejection fraction of <40%. The absolute and percentage of changes in inflammatory marker levels were evaluated using analysis of variance. Statin treatment reduced the concentrations of soluble tumor necrosis factor receptor-1 by 132 pg/ml (p = 0.04) and 8% (p = 0.056), C-reactive protein by 1.6 mg/L (p = 0.006) and 37% (p = 0.0002), and, after adjustment for treatment order, endothelin-1 by 0.21 pg/ml (p = 0.007) and 17% (p = 0.01). In post hoc analyses, the reduction in tumor necrosis factor receptor-1 levels was highest among patients with elevated levels at baseline (at or higher than the median of 1,055 pg/ml, p interaction = 0.001), among whom statin therapy reduced the levels by 306 pg/ml (p <0.001) and 22% (p <0.001). Statin treatment did not significantly affect the levels of other inflammatory markers, including interleukin-6 and brain natriuretic peptide. In conclusion, short-term atorvastatin therapy reduced the levels of several important inflammatory markers in patients with HF.
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PMID:The effects of atorvastatin (10 mg) on systemic inflammation in heart failure. 1636 Mar 60

Erectile dysfunction (ED) is associated with clinical atherosclerosis and several atherosclerotic risk factors including smoking, hypertension, dyslipidemia, diabetes mellitus, obesity and sedentary lifestyle. Clinical atherosclerosis is also associated with these same risk factors and with biomarkers of inflammation, thrombosis, endothelial cell activation. We evaluated the cross-sectional association between the degree of ED and levels of atherosclerotic biomarkers. A subcohort of 988 US male health professionals between the ages 46 and 81 years as part of an ongoing epidemiologic study had atherosclerotic biomarkers measured from blood collected in 1994-1995. These same men had in 2000, been retrospectively asked about erectile function in 1995 and in 2000. Biennial questionnaires since 1986 assessed medical conditions, medications, smoking, physical activity, body mass index, alcohol intake. The retrospective assessment of erectile function in 2000 for 1995 in these 988 men ranged from very good - 28.2%, good - 25.1%, fair - 19.2%, poor - 13.6%, to very poor - 13.9%. Men with poor to very poor erectile function compared to men with good and very good erectile function had 2.9 the odds of having elevated Factor VII levels (P=0.03), 1.9 times the odds of having elevated vascular cell adhesion molecule (P=0.13) and 2.0 times the odds of having elevated intracellular adhesion molecule (P=0.06) and 2.1 times the odds of having elevated total cholesterol/high-density lipoprotein ratio (P=0.02) comparing the top to bottom quintiles for each atherosclerotic biomarker after multivariate adjustment. Lipoprotein(a), homocysteine, interleukin-6 and tumor necrosis factor receptor, C-reactive protein and fibrinogen were not associated with the degree of erectile function after adjustment. We conclude that selected biomarkers for endothelial function, thrombosis and dyslipidemia but not inflammation are associated with the degree of ED in this cross-sectional analysis. Future studies evaluating the prospective association of ED, endothelial function and cardiovascular disease appear warranted.
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PMID:A retrospective study of the relationship between biomarkers of atherosclerosis and erectile dysfunction in 988 men. 1691 3


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