Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Yersinia enterocolitica infection in humans causes a broad spectrum of diseases ranging from acute bowel disease to extraintestinal manifestations such as reactive arthritis, erythema nodosum and uveitis. During the last decade a fascinating part of the molecular biology of the pathogenicity of human pathogenic Yersinia species has been unraveled. Pathogenicity factors such as protein tyrosine phosphatase, protein kinase, thrombin- and collagen-binding factors have been identified and characterized on the molecular level. In contrast to many animal models for human enteropathogenic microorganisms, experimental Y. enterocolitica infection in rodents resembles yersiniosis in humans and thus offers extraordinary opportunities to study the sequential steps of the infectious process. Rabbits are suitable animals in which to study Yersinia-induced enteritis (enterotoxin-mediated) and the humoral immune response after oral infection. The role of Peyer's patches (PP) in the entry of enteropathogenic Yersinia species has been elucidated in mice and rabbits. M cells are probably the primary target cells of invading Yersiniae. Surprisingly, after penetration of the mucosal epithelial cell layer Yersinia bacilli were visualized to be exclusively extracellular in PP tissue. Obviously neutrophils within PP were unable to phagocytize the invading microorganisms. Presently, it is not clear how the microorganisms disseminate from PP into lymph nodes, spleen, liver and lung of mice where they form abscesses and granuloma-like lesions. Immunohistologically the involvement of macrophages and T cells could be demonstrated in Yersinia-induced lesions of mice. Direct evidence for the role of T cells and cytokine-activated macrophages in the host defense reaction against a primary Yersinia infection in mice could be obtained from experiments including adoptive transfer of Yersinia-specific T cells and in vivo neutralization of TNF-alpha and IFN-gamma. The experimental rat model turned out to be a suitable model for studying Yersinia-induced aseptic arthritis. Lewis- and SHR rats proved to be arthritis-susceptible. Arthritogenicity of Yersinia for rats appeared to be restricted to Y. enterocolitica of serotype 08 and correlated with the virulence potential of this serotype. Surprisingly, expression of YadA, the collagen-binding factor, was not necessary for arthritis induction. A close association between both susceptibility to arthritis induction and Yersinia infection could be demonstrated in various rat strains. Depletion of alpha/beta T-cell receptor (alpha beta-TCR)-positive T cells by treatment with alpha beta-TCR-specific antibody revealed that T cells were required for clearance of the pathogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Experimental Yersinia enterocolitica infection in rodents: a model for human yersiniosis. 836 22

Abnormal cytokine levels have been described in patients with chronic liver disease, but studies correlating cytokine homeostasis with abnormalities in coagulation and fibrinolysis are lacking. In order to establish a link between cytokines and the hemostatic changes the following parameters were determined in 44 patients with cirrhosis (alcoholic = 15, postnecrotic = 22, others = 7): TNF-alpha, IL-6, thrombin-antithrombin (TAT) complexes, prothrombin fragment 1 + 2 (F1 + 2) and t-PA by using enzyme-linked immunosorbent assays, and PAI-1, plasminogen and alpha 2-antiplasmin (alpha 2-AP) by using chromogenic substrates. All patients were at stages B and C of Child's classification when entering the study. Mean cytokine concentrations were significantly higher in cirrhotic patients as compared to age- and sex-matched controls (p < 0.009). There was a significant increase of TAT (p < 0.02) and F1 + 2 (p < 0.001) in the patients groups, suggesting a grade of intravascular coagulation. A hyperfibrinolytic state as demonstrated by an increase of t-PA and decrease of plasminogen and alpha 2-AP was also observed (p < 0.001). We could define a subgroup of patients with cytokine values higher than 20 pg/ml. Interestingly, in this group there was a significant increase of TAT (p < 0.04) and t-PA (p < 0.02) levels and a decrease of plasminogen and alpha 2-AP (p < 0.02) as compared to values observed in patients with cytokines lower than 20 pg/ml. We conclude that high levels of TNF-alpha and IL-6 may contribute to hyperfibrinolysis and intravascular coagulation in patients with liver cirrhosis, as assessed by the increase of TAT and t-PA levels and the reduction of plasminogen and alpha 2-AP.
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PMID:Increased concentrations of tumor necrosis factor and interleukin-6 contribute to the hemostatic abnormalities in advanced liver disease. 858 22

The endothelial molecule thrombomodulin (TM) regulates hemostasis by binding thrombin and promoting conversion of protein C to activated protein C (aPC). Apart from its anticoagulant actions, aPC modulates mononuclear phagocyte (M phi) activation, including TNF-alpha production, indicating interrelationships of the coagulation and immune systems. While the endothelium is considered to be the prime regulator of aPC generation, TM recently has been identified M phi and neutrophils. This study analyzes TM membrane expression by human blood monocytes, alveolar macrophages, and U937 cells cultured in the presence of various stimuli. All except U937 cell expressed high levels of surface TM. Surprisingly, stimulation with LPS or TNF-alpha further up-regulated TM expression by M phi, whereas cultured endothelial cells (EC) showed decreased TM expression. However, noninflammatory stimuli induced qualitatively similar changes in M phi and EC; all-trans retinoic acid and prostaglandin E up-regulated surface TM, and PMA decreased TM expression. Changes in M phi TM expression were accompanied by alteration in functional activity. Thus, LPS increased the TM cofactor activity of THP-1 cells by 27 +/- 6.9% (p < 0.05), and PMA decreased their cofactor activity by 53.2 +/- 11.5% (p < 0.05).In addition, in vivo relevance was demonstrated by the presence of TM on intragraft inflammatory M phi during cardiac rejection, whereas adjacent EC lacked TM expression. These studies demonstrate that expression of TM on human M phi is regulated differently to EC with respect to inflammatory stimuli, suggesting the potential for extravascular M phi to promote local production of aPC.
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PMID:A physiologic anti-inflammatory pathway based on thrombomodulin expression and generation of activated protein C by human mononuclear phagocytes. 869 Sep 16

The effects of and interactions between the six inflammatory mediators interleukin-1 (IL-1), tumour necrosis factor (TNF), gamma-interferon (INF-gamma), transforming growth factor-beta (TGF-beta), bradykinin (BK) and thrombin on prostanoid biosynthesis in primary cultures of human, dental, pulp fibroblasts were examined. IL-1 alpha, IL-1 beta, TNF-alpha and TNF-beta caused a time- and concentration-dependent enhancement of prostaglandin E2 (PGE2) formation in the fibroblasts. The onset of action was delayed 1-2 h and maximal response was seen after 24 h. In contrast, BK and thrombin caused a burst of PGE2 formation with maximal response after 10 min. BK (1 microM) and thrombin (3 U/ml) synergistically potentiated IL-1 alpha and IL-1 beta stimulated PGE2 formation in 24 h cultures. The effect of BK and thrombin on IL-1 beta enhanced PGE2 formation was seen both at suboptimal and optimal concentrations of IL-1 beta without affecting the sensitivity to IL-1 beta. BK and thrombin also synergistically potentiated the stimulatory effect of TNF-alpha and TNF-beta on PGE2 formation. The synergistic interactions between BK and IL-1 alpha, IL-1 beta and TNF-alpha were seen after 2-4 h of treatment. BK analogues with affinity to BK B2-receptors, but not to BK B1-receptors, were able to synergistically potentiate IL-1 beta and TNF-alpha-enhanced PGE2 production. The synergistic stimulation of PGE2 formation by IL-1, TNF and BK was abolished by indomethacin and flurbiprofen. Preincubation with IL-1 beta and TNF-alpha for 24 h resulted in a substantial amplification of the PGE2 response to a subsequent 24 h challenge with BK in the absence of cytokine. Similarly, when the pulp fibroblasts were preincubated with or without IL-1 beta or TNF-alpha for 24 h and then challenged with exogenous arachidonic acid for 60 min, PGE2 formation was significantly enhanced in cytokine pretreated cells. BK potentiated cytokine induced amplification of the PGE2 response to arachidonic acid. gamma-IFN and TGF-beta did not enhance PGE2 formation, nor did these cytokines potentiate IL-beta or TNF-alpha-induced PGE2 production. These data show that proinflammatory mediators such as BK and thrombin act in concert with IL-1 and TNF in stimulating prostanoid formation in human pulpal fibroblasts and that the action of BK is linked to BK B2-receptors. The results are compatible with the view that enhanced metabolism of arachidonic acid, probably due to increased activation or de novo synthesis of cyclooxy-genase(s), is involved in the mechanism by which IL-1, TNF, BK and thrombin interact.
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PMID:Bradykinin and thrombin synergistically potentiate interleukin 1 and tumour necrosis factor induced prostanoid biosynthesis in human dental pulp fibroblasts. 877 76

Granzymes, serine proteases located in the granules of cytotoxic T cel ls and NK cells, are essential for induction of target cell apoptosis. However, since cytotoxic cells constitutively secrete a portion of their synthesized granzymes, these proteases could mediate extracellular functions independent of their role in the lytic event. Thrombin, another serine protease, can induce cytokine production in a number of different cell types. In this study, we test the hypothesis that granzymes, like thrombin, can regulate cell-mediated immunity by inducing the production of different cytokines. We show that granzyme A (GA) stimulates IL-6, IL-8, and TNF-alpha production by human PBMC and purified monocytes. In contrast, monocytes exposed to thrombin had enhanced IL-8 production with no induction of IL-6 or TNF-alpha production. However, monocytes exposed to either GA or thrombin had enhanced phagocytic activity. The enzymatic activity of GA and thrombin was required for the induction of cytokine production and for the enhancement of phagocytic activity. The induction of different cytokine profiles by GA vs thrombin suggested that GA activates monocytes via a receptor that was different from the thrombin receptor. This conclusion was strengthened by the fact that GA was incapable of inducing Ca2+ mobilization in insect cells transfected with the thrombin receptor. These results suggest that enzymatically active GA mediates important immunoregulatory functions through signaling pathways that does not involve thrombin receptor activation.
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PMID:Extracellular activities of human granzyme A. Monocyte activation by granzyme A versus alpha-thrombin. 878 23

The plasmin/plasminogen system of enzymes may be involved in leukocyte migration through the endothelial cell layer of the vascular wall during inflammatory processes associated with vascular injury, atherosclerosis, and sepsis. Synthesis of plasminogen activator inhibitor type 1 (PAI-1) by the endothelium may protect these cells and the subendothelial cell matrix from excessive degradation and retard leukocyte migration. We report in this work for the first time the down-regulation of both basal and thrombin- or endotoxin-induced PAI-1 in cultured human endothelial cells by the activated T cell product, IFN-gamma. Down-regulation of basal and thrombin- or endotoxin-induced endothelial PAI-1 protein by IFN-gamma was found to be both time and dose dependent. Decreases of up to 71% relative to thrombin- or endotoxin-treated controls, using an optimal IFN-gamma concentration of between 20 and 200 U/ml, were found for human macrovascular and microvascular endothelial cells. However, IFN-gamma did not appear to affect IL-1 alpha- and TNF-alpha-induced levels of PAI-1 protein or mRNA in these cells. Northern blot analysis paralleled protein results, showing decreases in specific endothelial cell thrombin- or LPS-induced PAI-1 mRNA expression, respectively, after incubation with IFN-gamma for 24 h. These results suggest a means by which the migration of circulating leukocytes through endothelial cell layers during inflammation may be facilitated.
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PMID:IFN-gamma inhibits thrombin- and endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells. 880 64

Using the Northern blot technique, we screened 6 human hepatoma cell lines to investigate the regulation mechanism of heparin cofactor II (HC II) biosynthesis. We found that HuH-7 and Hep G2 cells constitutively expressed the HC II gene. In conditioned medium, HuH-7 cells constantly produced HC II that was functionally active and formed a complex with thrombin in the presence of dermatan sulfate. HC II is thought be an acute phase reactant, and, therefore, we examined the effects of the major inflammatory cytokines, IL-6, IL-1 beta, and TNF-alpha, on the regulation of HC II production in HuH-7 and Hep G2 cells. In HuH-7 cells, the antigen and mRNA levels of plasminogen activator inhibitor type-1 (PAI-1), an acute phase protein produced by hepatocytes, were increased in response to stimulation with either IL-6 or IL-1 beta or both, but HC II antigen and mRNA levels were not changed by the same stimulation. Even when Hep G2 cells were treated with a combination of three cytokines, IL-6, IL-1 beta, and TNF-alpha, HC II antigen and mRNA levels were not changed; however, PAI-1 antigen and mRNA levels were clearly increased. These results suggest that the production of HC II in hepatoma cells is not regulated by the major inflammatory mediators, IL-6, IL-1 beta, and TNF-alpha.
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PMID:The production of heparin cofactor II is not regulated by inflammatory cytokines in human hepatoma cells: comparison with plasminogen activator inhibitor type-1. 881 80

Cerebral ischemia is caused by reduced blood supply at the microcirculatory level. In the microvessels, the main elements of the reperfusion injury following brain ischemia are the transformation of endothelial cell-surface from anticoagulant to procoagulant property, leukocyte adhesion, sludge or clot formation. There is a paucity of information on how hemostatic factors, cytokines, lipoprotein(a) (Lp(a)) and endothelin-1 (ET-1), being responsible for ischemic/reperfusion injury, interact with human brain microvessel endothelium (HBEC). There are no data furthermore about the expression of complement proteins of HBEC influenced by cytokines or fibrinolytic factors. Previously we established optimal conditions for culturing HBEC. Cell contraction induced by thrombin, plasmin, miniplasmin was recorded. The reassembly of F-actin was observed after thrombin treatment. ICAM-1 upregulation was measured following TNF-alpha, IL-1-alpha and thrombin incubation. Plasmin and miniplasmin downregulated the ICAM-1 in our cell culture system. Lp(a) modulated the thromboresistant cell-surface by reduction of t-PA and u-PA, but PAI-1 remained unchanged. Lp(a) modulated the ET-1 production by early increasing and late decreasing, in a bimodal manner. The increased secretion of ET-1 by cytokines (TNF-alpha, IL-1-alpha) was reduced in the presence of Lp(a). Gradual increase of complement proteins (factor H, factor B, C4) was induced by cytokines. Plasmin and miniplasmin augmented a rapid increase of C4. Some factors of complex relationship between regulators and modulators of endothelial adhesion molecules have been demonstrated in a human cell culture system prepared from brain microvessel endothelium. A unified concept of sequential events of ischemia/reperfusion in the brain has not yet developed.
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PMID:Human brain microvessel endothelial cell culture as a model system to study vascular factors of ischemic brain. 889 62

Multiple organ dysfunction syndrome (MODS) is a critical condition developing in the patients under overwhelming surgical insults such as a major surgery, severe trauma, extensive burn, and systemic sepsis. The host response to those surgical insults is the main pathogenetic factor contributing to the development of shock and MODS seen in surgical patients. The proinflammatory cytokines, TNF-alpha (TNF) and interleukin-1 beta (IL-1), are known to play a pivotal role in the pathogenetic mechanisms of MODS. In response to surgical insults, macrophages produce and release TNF and IL-1 which subsequently induce the production of other cytokines (IL-6, IL-8, etc.) and other endogenous chemical mediators (growth factors, adhesion molecules, complement cleavage products, thrombin, eicosanoids, PAF, nitric oxides, oxygen-free radicals, granulocyte elastase, etc.) The resultant systemic inflammation may develop into shock and MODS when the primary insults are overwhelming (early MODS) or a second inflammatory insult such as sepsis triggers an exaggerated inflammation. In the patients suffering from MODS, a systemic release of various cytokines is not properly regulated, and the high blood levels of the proinflammatory cytokines induce an autodestructive generalized inflammatory reaction. This condition is termed "Cytokine Storm" by the author. In the cytokine storm, not only proinflammatory cytokines but also anti-inflammatory cytokines are elevated in the blood stream. With the recent understanding of the biological and pathological roles of cytokines and other mediators, a new therapeutic strategy has been developed. In addition to the reduction of the surgical insults, a variety of anti-cytokine therapy and anti-mediator therapy has been tested in an attempt to prevent or treat the life-threatening MODS.
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PMID:[Cytokine storm in the pathogenesis of multiple organ dysfunction syndrome associated with surgical insults]. 894 Jun 90

Inflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma are increased in sera and lesions of Kaposi's sarcoma (KS) patients. Previous data have indicated that the combination of these cytokines as found in conditioned media from activated T cells induces normal endothelial cells to acquire the features of KS spindle cells (KS cells) including spindle morphology, marker expression, and the responsiveness to the effects of HIV-1 Tat protein. Conditioned media from activated T cells or the single cytokines also induce AIDS-KS cells to produce and release basic fibroblast growth factor (bFGF). bFGF is highly expressed also by in situ KS cells and mediates KS-like lesion formation after inoculation of the cells in nude mice. Here we show that both large and small vessel endothelial cells chronically exposed to inflammatory cytokines produce and release bioactive bFGF in the absence of cell death. In addition, after this treatment, endothelial cells acquire angiogenic capability and induce KS-like lesions after inoculation in nude mice. Production and release of bFGF is induced in a synergistic fashion by TNF-alpha, IL-1beta, and IFN-gamma, and its release is further promoted by low cell density and by the serine proteases plasmin and thrombin. These results indicate that inflammatory cytokines induce endothelial cells to export bFGF and to acquire angiogenic properties, a key feature of the KS cell phenotype, and suggest a mechanism by which these cytokines can cooperate in the induction of KS.
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PMID:Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice. 902 30


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