Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

gC1q-R is a 33 kDa, single chain, highly acidic protein, which was first isolated from membrane preparation of Raji cells and now appears to be ubiquitously distributed. Although, gC1q-R was originally identified as a protein which binds to the globular "heads" of C1q, recent evidence suggests that the molecule is in fact a multiligand binding, multifunctional protein with affinity for diverse ligands which at best are functionally related. These molecules include: thrombin, vitronectin, and high molecular weight kininogen. The gC1q-R molecule, which is identical to the transcription factors SF2 and the Tat-associated protein, or TAP, is the product of a single gene localized on chromosome 17p13.3 in human, and chromosome 11 in mouse, and is encoded by an approximately 1.5-1.6 kb mRNA. The full length cDNA encodes a primary translation protein of 282 residues and the 'mature' or membrane form of the protein isolated from Raji cells corresponds to residues 74-282 and is presumed to be generated by a site-specific cleavage and removal of the highly basic, 73-residues long, N-terminal segment during post-translational processing. The translated amino acid sequence does not predict for the presence of a conventional sequence motif compatible with a transmembrane segment and does not have a consensus site for a GPI anchor. However, there is strong evidence which indicates that gC1q-R is expressed both inside the cell and on the membrane. First, certain mAbs raised against gC1q-R react moderately with intact Raji cells in suspension and this binding increases when the cells are first bound to poly-L-lysine coated surfaces and then fixed with glutaraldehyde. Second, surface labeling of cells using the membrane impermeable sulfo-NHS-LC-biotin shows that gC1q-R on the surface incorporates biotin whereas intracellular gC1q-R does not. In addition, the membrane expression of gC1q-R can be upregulated with inflammatory cytokines such as INF-gamma, TNF-alpha, or LPS. These results suggest, that gC1q-R, is localized both as an intracellular and as a cell surface protein and may have important biological functions in both compartments of the cell.
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PMID:Structure and function of gC1q-R: a multiligand binding cellular protein. 977 8

Proinflammatory effects induced by the serine protease factor Xa were investigated in HUVEC. Exposure of cells to factor Xa (5-80 nM) concentration dependently stimulated the production of IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) and the expression of E-selectin, ICAM-1, and VCAM-1, which was accompanied by polymorphonuclear leukocyte adhesion. The effects of factor Xa were blocked by antithrombin III, but not by the thrombin-specific inhibitor hirudin, suggesting that factor Xa elicits these responses directly and not via thrombin. IL-1alpha and TNF-alpha were not implicated, since neither the IL-1 receptor antagonist nor a TNF-neutralizing Ab could suppress the factor Xa responses. Active site-inhibited factor Xa and factor Xa depleted from gamma-carboxyglutamic acid residues were completely inactive. The effector cell protease receptor-1 (EPR-1) seems not to be involved since anti-EPR-1 Abs failed to inhibit cytokine production. Moreover, neither the factor X peptide Leu83-Leu88, representing the inter-epidermal growth factor sequence in factor Xa that mediates ligand binding to EPR-1, nor the peptide AG1, corresponding to the EPR-1 sequence Ser123-Pro137 implicated in factor Xa binding, inhibited the factor Xa-induced cytokine production. In conclusion, these findings indicate that factor Xa evokes a proinflammatory response in endothelial cells, which requires both its catalytic and gamma-carboxyglutamic acid-containing domain. The receptor system involved in these responses induced by factor Xa remains to be established.
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PMID:Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. 978 Feb 8

Prostaglandins are involved in force-induced orthodontic tooth movement. Bradykinin (BK) and thrombin are known to cause a significant time- and concentration-dependent burst of prostanoid biosynthesis in cultured human periodontal-ligament (PDL) cells. The aim now was to investigate interactive effects between interleukin 1 alpha, -beta (IL-1 alpha, -1 beta), tumour necrosis factor-alpha,-beta (TNF-alpha, -beta) and BK or thrombin on prostaglandin biosynthesis in human PDL cells. IL-1 alpha and -1 beta produced time- and concentration-dependent stimulation of prostanoid biosynthesis [prostaglandin (PG)E2 and 6-keto-PGF1alpha]. Synergistic stimulation of prostanoid biosynthesis was demonstrated when BK or thrombin were added together with IL-1 alpha or -1 beta. BK and IL-1 beta both significantly stimulated the release of [3H]arachidonic acid. No synergistic effect on [3H]arachidonic acid release was seen when BK and IL-1 beta were added simultaneously. These data suggest that the synergistic effect of BK and IL-1 beta on prostanoid biosynthesis is not due to interactions at the receptor level nor to enhanced release of arachidonic acid, but may be due to increased activity of cyclo-oxygenase. Also, TNF-alpha and -beta produced a concentration-dependent stimulation of PGE2 formation in cultured human PDL cells. Synergistic effects of BK and thrombin were demonstrated when PGE2 production was stimulated in combination with TNF-beta. In addition, a synergistic effect on the PGE2 response to IL-1 alpha or -1 beta was demonstrated when added in combination with TNF-alpha. These experiments demonstrate synergistic interactions between BK, thrombin, IL-1 and TNF on prostaglandin biosynthesis in cultured human PDL cells. The findings suggest that inflammatory mediators may act in concert in stimulating prostanoid production in response to pro-inflammatory stimuli. As an inflammatory reaction is seen in the periodontal ligament when teeth are orthodontically treated, this synergistic interaction may be of importance in force-induced tooth movement.
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PMID:Synergistic interactions of bradykinin, thrombin, interleukin 1 and tumor necrosis factor on prostanoid biosynthesis in human periodontal-ligament cells. 983

The ganglioside GM1 is known to play a pivotal role in neuronal survival and/or regeneration. Recently it has been shown that GM1 binds tightly with membrane-bound amyloid beta protein (A beta) and prevents its conversion from a helical to a beta-sheet structure. To examine the potential physiological consequences of this binding, we studied the effect of GM1 on A beta-stimulated release of proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and TNF-alpha, using the human monocytic cell line, THP-1, as a model system. Treatment of THP-1 cells with A beta 1-40 or A beta 25-35 resulted in an increased cytokine release from these cells. However, treatment of A beta-activated THP-1 cells with GM1 and several other complex gangliosides, but not hematosides and neutral glycosphingolipids such as asialo-GM1 (GA1), lactosylceramide, and globoside, significantly decreased the cytokine release. In contrast, this effect was not observed for lipopolysaccharide (LPS)-activated and thrombin-activated THP-1 cells, indicating that the ganglioside effect is specific for A beta-induced cytokine release. A direct interaction between GM1 and A beta was demonstrated using the surface plasmon resonance technique. We found that GM1 ganglioside exhibited higher affinity for A beta 1-40 than GA1, suggesting that the sialic acid moiety of GM1 is necessary for its interaction with A beta. We conclude that the inhibitory effect of GM1 on A beta-induced cytokine release may reflect pre-existing abnormalities in membrane transport at the stage of amyloid formation and that GM1 may induce conformational changes in A beta, resulting in diminished fibrillogenesis and prevention of the inflammatory response of neuronal cells in Alzheimer's disease.
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PMID:GM1 inhibits amyloid beta-protein-induced cytokine release. 997 68

Sepsis is commonly associated with disturbances of the hemostatic balance. Most of the pathophysiological changes in sepsis are caused by endotoxin acting directly through endothelial injury or indirectly through release of cytokines with procoagulant effects. The relation between cytokines and hemostatic parameters was assessed in 32 patients with sepsis. Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complexes (TAT), tissue type plasminogen activator (t-PA) functional and antigen, plasminogen activator inhibitor-1 (PAI-1), plasminalpha2-antiplasmin complexes (PAP), D-Dimer, thrombomodulin (TM) and von Willebrand factor (vWF) were measured in patients and in 30 healthy subjects. The levels of cytokines TNF-alpha and interleukin-6 (IL-6) also were determined. A significant increase of F1+2, TAT, PAI-1, PAP, and D-Dimer was observed in septic patients as compared with controls (p<0.0001), whereas t-PA activity was significantly reduced (p<0.01). The markers of endothelial cell activation TM, vWF, and t-PA antigen also were elevated significantly as compared with the control group (p<0.01). Finally, we found a marked increase of TNF-alpha and IL-6 (p<0.0001). Whereas the increase of cytokine levels could be partially responsible for the hemostatic activation, it did not correlate with markers of endothelial activation in patients with sepsis.
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PMID:Endothelial cell and hemostatic activation in relation to cytokines in patients with sepsis. 1023 Aug 94

Incubation of cultured human umbilical vein endothelial cells (HUVECs) with dilutions of peritoneal dialysis effluents (PDEs) from 11 individual patients undergoing continuous ambulatory peritoneal dialysis (CAPD) induced cellular procoagulant activity in a dose and time dependent manner. This procoagulant activity could be attributed to tissue factor (TF) expression since it was blocked by rabbit anti-TF IgG. These data was confirmed by FACS analysis yielding surface TF expression; In addition PDEs induced the expression of E-selectin in HUVECs. This TF and selectin inducing activity was heat labile and could be inhibited by protease inhibitors. Partial purification could be achieved using a benzamidine-Sepharose column. The TF inducing activity could not be attributed to LPS, IL-1, TNF-alpha, mast cell tryptase, active thrombin, or complement factor D. We therefore conclude that the peritoneal cavity contains a protease activity that induces a procoagulatory and proinflammatory phenotype in HUVECs.
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PMID:Protease dependent activation of endothelial cells by peritoneal dialysis effluents. 1054 24

Direct adsorption of lipoproteins (DALI) is the first lipid apheresis system compatible with whole blood with the advantage of a very simple procedure. A mixture of heparin plus citrate (ACD-A) is used for the anticoagulation regimen (AR). A clinical, prospective, controlled crossover study was performed to test the safety and efficacy of low-dose citrate (LDC) anticoagulation in DALI. Five chronic DALI patients suffering from coronary heart disease and hypercholesterolemia underwent 3 DALI sessions each using the LDC anticoagulation regimen (60 IU heparin/kg body weight as initial bolus; 1:40 ACD-A: blood as perfusion). This was compared to 3 sessions per patient with the standard AR (bolus of 20 IU heparin/kg, 1:20 ACD-A as perfusion). Patient blood volumes (1.6; average of 7,040 ml) were treated with 750 ml adsorber gel per session at a blood flow rate of 60 ml/min. Mean LDL and Lp(a) reductions exceeded 60% with both AR. No clinical side effects were observed. Both AR controlled the coagulation well as evidenced by a sufficient prolongation of the partial prothrombin time (PTT) and activated clotting time as well as low thrombin-antithrombin (TAT) formation. Biocompatibility parameters exhibited favorable results (low activation of complement and cells, and only slight formation of C3a, C5a, beta-thromboglobulin, elastase, and TNF-alpha). The asymptomatic bradykinin generation was comparable in both study arms. LDC optimized the ionized calcium levels and pH in the efferent blood postadsorber. LDC anticoagulation was safe and effective, and may further improve the tolerance of DALI apheresis in hypercholesterolemic patients.
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PMID:Effect of low-dose citrate anticoagulation on the clinical safety and efficacy of direct adsorption of lipoproteins (DALI apheresis) in hypercholesterolemic patients: a prospective controlled clinical trial. 1109 Nov 68

Thrombomodulin (TM), a membrane-bound receptor for thrombin on the endothelial cell surface, contributes to the regulation of the coagulation system. TM is known to exist in human plasma and urine as soluble forms. We purified soluble TM from human urine (MR-33) and investigated the anticoagulant effects of MR-33 in vitro and in vivo. In human plasma, MR-33 inhibited not only the procoagulant activity of thrombin, but also the thrombin generation via accelerating the thrombin-catalyzed protein C activation. In rat disseminated intravascular coagulation (DIC) models, intravenous infusion of MR-33 improved the hematological abnormalities without excessive prolongation of APTT and bleeding time. Benefit (dose required for 50% inhibition of fibrinogen decrease: ED50) to risk (minimum dose required for significant prolongation of bleeding time) ratio was 1:27 for MR-33. Furthermore, the anticoagulant activities of MR-33 was independent of AT III activity, and MR-33 was effective on heparin-resistant DIC models with low AT III level in rats. Intravenous injection of MR-33 prevented the endotoxin-induced increases in TAT, TNF-alpha and IL-6 level and pulmonary vascular permeability in mice. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage, and this drug also has anti-inflammatory effects. Clinical trials of MR-33 for the treatment of DIC are now in progress in Japan.
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PMID:[Thrombomodulin]. 1121 78

Thrombin is a procoagulant and proinflammatory molecule in vivo. In vitro, thrombin has been shown to induce endothelial activation, notably IL-8 secretion and adhesion molecule expression. In this study, we showed that thrombin may induce a new cascade leading from acute to chronic inflammation. Thrombin was able to induce the production of both IL-6 and monocyte chemotactic protein-1 (MCP-1) by HUVEC independently of IL-1alphabeta and TNF-alpha. Addition of physiological concentrations of exogenous soluble IL-6Ralpha (sIL-6Ralpha) to thrombin-activated HUVEC was sufficient to increase the amounts of MCP-1 produced, but not those of IL-8. These effects could be blocked by anti-IL-6 or anti-sIL-6Ralpha blocking mAb, demonstrating the existence of an autocrine loop of MCP-1 secretion, involving the IL-6/IL-6Ralpha/gp130 complex on HUVEC. In addition, we identified IL-8-activated neutrophils as a potential source of sIL-6Ralpha because IL-8 induced IL-6Ralpha shedding from the neutrophil membranes and increased in parallel sIL-6Ralpha concentrations in neutrophil supernatants. Furthermore, addition of neutrophils to thrombin-activated HUVEC significantly increased MCP-1 secretion, which could be decreased by blocking IL-6. Thus, thrombin-activated endothelium may induce a cascade of events characterized by IL-8 secretion, neutrophil local infiltration, and the release of IL-6Ralpha from neutrophil membranes. sIL-6Ralpha may then complex with IL-6 and increase the amount of MCP-1 produced by thrombin-activated endothelium, favoring monocyte infiltration, and the transformation of acute into chronic inflammation.
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PMID:The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. 1154 36

Because activation of the coagulation cascade and the generation of thrombin coexist with sepsis and the release of tumor necrosis factor (TNF)-alpha, we determined the effects of TNF-alpha on the mechanism of thrombin-induced increase in endothelial permeability. We assessed Ca(2+) signaling in human umbilical vein endothelial cells. In human umbilical vein endothelial cells exposed to TNF-alpha for 2 h, thrombin produced a rise in the intracellular Ca(2+) concentration ([Ca(2+)](i)) lasting up to 10 min. In contrast, thrombin alone produced a rise in [Ca(2+)](i) lasting for 3 min, whereas TNF-alpha alone had no effect on [Ca(2+)](i.) Thrombin-induced inositol 1,4,5-trisphosphate generation was not different between control and TNF-alpha-exposed cells. In the absence of extracellular Ca(2+), thrombin produced similar increases in [Ca(2+)](i) in both control and TNF-alpha-exposed cells. In TNF-alpha-exposed cells, the thrombin-induced Ca(2+) influx after intracellular Ca(2+) store depletion was significantly greater and prolonged compared with control cells. Increased Ca(2+) entry was associated with an approximately fourfold increase in Src activity and was sensitive to the Src kinase inhibitor PP1. After TNF-alpha exposure, thrombin caused increased tyrosine phosphorylation of junctional proteins and actin stress fiber formation as well as augmented endothelial permeability. These results suggest that TNF-alpha stimulation of endothelial cells results in amplification of the thrombin-induced Ca(2+) influx by an Src-dependent mechanism, thereby promoting loss of endothelial barrier function.
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PMID:Synergistic effects of tumor necrosis factor-alpha and thrombin in increasing endothelial permeability. 1155


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