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)

The precise mechanisms leading to the coagulopathy of acute liver injury are unclear. To study this further, coagulation and immune changes have been compared in patients with acute liver injury secondary to paracetamol overdose, with chronic cirrhosis, and normal healthy controls. In acute liver injury, coagulation factors II, V, VII and X were reduced to a similar degree, and were significantly lower than factors IX and XI. In cirrhosis, by contrast, these coagulation factors were reduced to similar levels. Factor VIII increased in acute liver injury, but was normal in cirrhosis. Interleukin-6 and tumour necrosis factor-alpha levels increased in both patient groups, but were higher in paracetamol overdose. Thrombin-antithrombin and soluble tissue factor levels increased in those with acute liver injury, but were normal in patients with cirrhosis. Functional antithrombin was reduced in both acute liver injury and cirrhosis. It is hypothesized that in acute paracetamol-induced liver injury, immune activation leads to tissue factor-initiated consumption of factors II, V, VII and X, but that levels of factors IX and XI are better preserved because of inhibition of the thrombin-induced amplification phase of coagulation. These findings have implications for appropriate coagulation factor support for patients with acute liver injury.
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PMID:New insights into haemostasis in liver failure. 1456 36

Activated platelets facilitate thrombin generation by providing a catalytic surface on which coagulation activation occurs. The glycoprotein (GP) IIb/IIIa receptor might play a major role in this process as shown by in vitro and animal experiments. However, it is controversial whether the GPIIb/IIIa receptor facilitates tissue factor-induced thrombin generation in humans as well. We therefore investigated whether two clinically used GPIIb/IIIa antagonists (tirofiban and eptifibatide) may blunt TF-induced coagulation in humans. Thirty male volunteers received 2 ng/kg endotoxin and standard doses of eptifibatide, tirofiban or placebo over 5 hours in a randomized, double-blind, placebo-controlled, double-dummy parallel-group trial. Markers of thrombin generation (prothrombin fragment 1+2, thrombin-antithrombin complexes), fibrinolysis (D-dimer, plasmin-antiplasmin complexes) as well as inflammatory markers (interleukin-6, tumor necrosis factor-alpha) were measured by enzyme linked immunoasssays, TF-mRNA expression was quantified by RT-PCR. Neither eptifibatide nor tirofiban influenced LPS-induced coagulation activation or fibrinolytic activity. Additionally, the increase of TNF-alpha and IL-6 was similar in all groups. In conclusion, GPIIb/IIIa blockade with eptifibatide or tirofiban did not influence TF-induced coagulation activation in human low grade endotoxemia.
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PMID:Blockade of GPIIb/IIIa by eptifibatide and tirofiban does not alter tissue factor induced thrombin generation in human endotoxemia. 1465 36

The objective of this study was to investigate the difference between the closed circuit system and the open circuit system in clinical heparin-coated cardiopulmonary bypass (CPB) circuits with a centrifugal pump. We evaluated the coagulation, fibrinolysis, and inflammatory response in valvular heart surgery. Nineteen patients were assigned at random to a group for the closed circuit system or the open circuit system. This is the first report on the effect of a closed circuit in valvular surgery. We measured the platelet count, white blood cell count, plasma fibrinogen concentration, thrombin-antithrombin III complex, plasmin-Alpha2 plasmin inhibitor complex, D-dimer, interleukin-6, polymorphic neutrophil-elastase, and the plasma free hemoglobin. Blood samples were collected before the start of perfusion, 15 and 60 min after the start of perfusion, 60 min after the administration of protamine, and 1 day after the operation. During the perfusion, coagulation, fibrinolysis, and inflammatory responses were activated; however, no significant differences between the two groups were noted. In this clinical investigation with suction and the cell saving system, the closed circuit was not found to be superior to the open circuit with regard to biocompatibility.
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PMID:Clinical study of biocompatibility between open and closed heparin-coated cardiopulmonary bypass circuits. 1469 66

Opiate addicts have been shown to have a high susceptibility to bacterial infection. We investigated how treatment with morphine alters lipopolysaccharide (LPS)-induced inflammatory responses in the rat. Chronic morphine alone elevated serum endotoxin levels. Animals treated with morphine and LPS (250 microg/kg) developed hypothermia, decreased mean arterial pressure (MAP), increased plasma thrombin anti-thrombin III (TAT) complex, and approximately 67% of animals exhibited progressive intramicrovascular coagulation. Morphine also enhanced LPS-induced leukocyte-endothelial adhesion (LEA), suppressed leukocyte flux, and corticosterone production, and elevated interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 serum levels. Our study presents both the molecular and cellular mechanisms underlying the potentiated LPS-induced inflammation and accelerated progression to septic shock seen with chronic morphine exposure.
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PMID:Chronic morphine accelerates the progression of lipopolysaccharide-induced sepsis to septic shock. 1502 69

Inhibition of the tissue factor-factor VIIa complex reduces coagulation and inflammation in animal models of endotoxemia and sepsis and in patients with severe sepsis. However, the mechanism by which tissue factor-dependent activation of the coagulation cascade enhances inflammation is not known. We tested the hypothesis that coagulation proteases enhance inflammation during endotoxemia by activating protease-activated receptors (PARs) within the vasculature. We found that genetically modified mice expressing low levels of tissue factor exhibited reduced interleukin-6 expression and increased survival in a mouse model of endotoxemia compared with control mice. In contrast, hirudin inhibition of thrombin or a deficiency in either PAR-1 or PAR-2 did not affect interleukin-6 expression or mortality. However, combining hirudin treatment to inhibit thrombin signaling through PAR-1 and PAR-4 with PAR-2 deficiency reduced lipopolysaccharide-induced interleukin-6 expression and increased survival. Taken together, our results suggest that activation of multiple PARs by coagulation proteases enhances inflammation during endotoxemia.
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PMID:Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis. 1511 33

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, statins, have been demonstrated to reduce cardiovascular morbidity and mortality in patients with a wide range of cholesterol levels. Numerous cholesterol-independent effects of statins that may limit atherosclerosis are probably related to inhibition of the geranylgeranylation of GTP-binding intracellular signaling proteins and involve: improved vasoreactivity, mostly through increased NO bioavailability; decreased expression of proinflammatory cytokines (interleukin-6, interleukin-1 beta, tumor necrosis factor alpha), C-reactive protein, chemokines, matrix metalloproteinases, and tissue factor with the subsequent inhibition of thrombin generation; reduced platelet activity; increased thrombomodulin expression; enhanced fibrinolysis, regulation of angiogenesis and immunomodulation. However, the clinical relevance of multiple protective effects induced by statins has not been clarified yet.
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PMID:New nonlipid effects of statins and their clinical relevance in cardiovascular disease. 1517 91

Human gingival fibroblasts (HGFs) express protease-activated receptor-1 (PAR-1) at high levels. In cultured HGFs, we studied the signaling pathway of thrombin-induced interleukin-6 (IL-6) production. The PAR-1 agonist peptide SFLLRN mimicked the thrombin-induced IL-6 production in the presence of amastatin, an aminopeptidase inhibitor. Thrombin or a combination of SFLLRN and amastatin also strikingly induced the expression of IL-6 mRNA. Although continuous exposure of HGFs to thrombin rapidly desensitized Ca(2+) signaling, the cells did not lose their ability to produce IL-6 in response to thrombin. Similarly, although treatment of HGFs with BAPTA-AM [1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester], an intracellular Ca(2+) chelator, markedly attenuated the thrombin-induced increase in intracellular Ca(2+) concentration, the same treatment did not suppress the thrombin-induced IL-6 production. However, thrombin-induced IL-6 production was strongly inhibited by the p38 mitogen-activated protein (MAP) kinase and tyrosine kinase inhibitors, and Western blotting analyses showed that thrombin stimulates p38 MAP kinase phosphorylation. Specific inhibitors that inhibit extracellular signal-regulated kinase 1/2 kinase, phosphatidylinositol 3-kinase, and RhoA kinase also partially suppressed the thrombin-induced IL-6 production, but the effects were smaller than those of the p38 MAP and tyrosine kinase inhibitors. Thus, thrombin induces HGFs to produce IL-6 by activating PAR-1, and the tyrosine kinase- and p38 MAP kinase-dependent pathways, rather than the Ca(2+) signaling pathway, may play a crucial role in the IL-6 production.
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PMID:Signaling mechanisms involved in protease-activated receptor-1-mediated interleukin-6 production by human gingival fibroblasts. 1521 Aug 34

In addition to their role in cytokine gene regulation in T cells, nuclear factors of activated T cells (NFATs) have been shown to be involved in cardiac development and hypertrophy. We have reported previously that NFATs play an important role in the regulation of vascular smooth muscle cell (VSMC) proliferation by receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) agonists, platelet-derived growth factor-BB (PDGF-BB) and thrombin, respectively. To understand the role of NFATs in vascular disease and development, we have now studied the role of these transcriptional factors in VSMC motility. PDGF-BB and thrombin induced VSMC motility in a dose-dependent manner. Blockade of NFAT activation resulted in substantial reduction in PDGF-BB- and thrombin-induced VSMC motility. PDGF-BB and thrombin also induced interleukin-6 (IL-6) expression in NFAT-dependent manner. Furthermore, IL-6 dose-dependently caused VSMC motility. A neutralizing anti-rat IL-6 antibody inhibited VSMC motility induced by IL-6, PDGF-BB, and thrombin. In addition, exogenous addition of IL-6 rescued both PDGF-BB- and thrombin-induced VSMC motility from inhibition by the blockade of NFAT activation. Together, these results for the first time demonstrate that NFATs mediate both RTK and GPCR agonist-induced VSMC motility via induction of expression of IL-6.
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PMID:A novel role for nuclear factor of activated T cells in receptor tyrosine kinase and G protein-coupled receptor agonist-induced vascular smooth muscle cell motility. 1527 6

The single nucleotide polymorphism (SNP) Ser128Arg in the E-selectin gene is overrepresented in certain patient groups with atherosclerosis or restenosis. We hypothesized and tested whether it may affect cytokine-induced levels of soluble (s) E-selectin, or be associated with proinflammatory or procoagulant properties in a well-standardized inflammation model. Healthy male volunteers (n = 157) received a lipopolysaccharide (LPS) infusion and were genotyped for the S128R SNP, and outcome parameters were measured by enzyme immunoassays and real-time polymerase chain reaction (RT-PCR, Taqman). The S128R SNP had no pronounced effects on basal or inducible sE-selectin levels, or levels of tumor necrosis factor or interleukin-6. However, carriers of the S128R SNP had 20% higher monocyte counts at 24 hours after LPS infusion. Importantly, the S128R allele enhanced thrombin generation by 50% to 80%, as measured by prothrombin fragment F(1+2) (P < .01), and hence fibrin formation (D-dimer) 2-fold (P = .01 to P = .002). However, tissue factor (TF) mRNA levels were not affected. The S128R E-selectin genotype is associated with procoagulant effects in a human model of endotoxin-induced, TF-triggered coagulation. This could contribute to its linkage with various thrombotic cardiovascular disorders.
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PMID:The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia. 1554 47

The principles of Virchov's triad appear to be operational in atherothrombosis or arterial thrombosis: local flow changes and particularly vacular wall damage are the main pathophysiological elements. Furthermore, alterations in arterial blood composition are also involved although the specific role and importance of blood coagulation is an ongoing matter of debate. In this review we provide support for the hypothesis that activated blood coagulation is an essential determinant of the risk of atherothrombotic complications. We distinguish two phases in atherosclerosis: In the first phase, atherosclerosis develops under influence of "classical" risk factors, i.e. both genetic and acquired forces. While fibrinogen/fibrin molecules participate in early plaque lesions, increased activity of systemic coagulation is of no major influence on the risk of arterial thrombosis, except in rare cases where a number of specific procoagulant forces collide. Despite the presence of tissue factor - factor VII complex it is unlikely that all fibrin in the atherosclerotic plaque is the direct result from local clotting activity. The dominant effect of coagulation in this phase is anticoagulant, i.e. thrombin enhances protein C activation through its binding to endothelial thrombomodulin.The second phase is characterized by advancing atherosclerosis, with greater impact of inflammation as indicated by an elevated level of plasma C-reactive protein, the result of increased production influenced by interleukin-6. Inflammation overwhelms protective anticoagulant forces, which in itself may have become less efficient due to down regulation of thrombomodulin and endothelial cell protein C receptor (EPCR) expression. In this phase, the inflammatory drive leads to recurrent induction of tissue factor and assembly of catalytic complexes on aggregated cells and on microparticles, maintaining a certain level of thrombin production and fibrin formation. In advanced atherosclerosis systemic and vascular wall driven coagulation becomes more important and elevated levels of D-dimer fragments should be interpreted as markers of this hypercoagulability.
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PMID:Blood coagulation and the risk of atherothrombosis: a complex relationship. 1557 98


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