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

---

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

Megakaryocytopoiesis concerns the commitment of hematopoietic stem cells towards the megakaryocyte lineage, the proliferation and maturation of megakaryocyte progenitors, leading to platelet formation. Normal megakaryocytopoiesis requires an equilibrium between positive and negative regulators. Thrombopoietin, recently cloned, is the main growth factor for the megakaryocyte lineage, enhancing all the steps of megakaryocyte development: proliferation, maturation, ploidisation, platelet formation. Several other factors have a direct (interleukin 3, 6, 11, 13, GMCSF, erythropoietin) or indirect (interleukin 1, stem cell factor) positive effect. Factors inhibiting megakaryocytopoiesis are synthetized by the megakaryocytes themselves (platelet factor 4, transforming growth factor beta), or have many other effects (alpha-interferon, thrombin) or correspond to a novel molecule (anagrelide). Heparin and other glycosaminoglycans positively modulate megakaryocytopoiesis by acting synergistically with some growth factors and by neutralizing some inhibitors. These progresses in the knowledge of normal and pathological megakaryocytopoiesis should lead to considerable therapeutic advances.
...
PMID:[Positive and negative regulation of megakaryocytopoiesis]. 907 17

We investigated the role of the thrombomodulin (TM/protein C/protein S anticoagulant pathway in modulating the thrombogenic properties of the endothelium. Endothelial cells (ECs) were placed in parallel-plate flow chambers and exposed to nonanticoagulated human blood at a venous wall shear rate (50 s-1). Fibrin deposition on resting ECs treated with a control IgG1 was negligible. In contrast, a significant amount of fibrin deposited when TM expression was specifically suppressed by > 95% by preincubating ECs with an anti-TM IgG1. Similarly, fibrin deposited on interleukin 1-stimulated ECs, but the fibrin deposition was further increased threefold with anti-TM IgG1. Comparable results were found when ECs were perfused at 650 s-1. When TM surface activity was enhanced by 150% by treating ECs with active phorbol ester (4-phorbol 12-myristate 13-acetate; PMA), the deposition of fibrin was 30% lower than on ECs not pretreated with PMA. Finally, fibrin deposition on stimulated ECs was significantly higher in 11 untreated patients with well-characterized deficiencies of protein C or S or heterozygous factor V Leiden mutation than in 11 healthy individuals, and it was significantly correlated to basal plasma levels of thrombin-antithrombin complexes. Thus, this study underlines the central role of the TM/protein C/protein S pathway in modulating the thrombogenic status of resting and stimulated ECs and indicates that basal coagulation system markers may be helpful in monitoring patients presenting a disorder of this anticoagulant pathway.
...
PMID:The thrombomodulin/protein C/protein S anticoagulant pathway modulates the thrombogenic properties of the normal resting and stimulated endothelium. 910 71

In addition to its role in coagulation, thrombin is involved in the inflammatory process by inducing vessel neutrophilic infiltration. Thrombin induces endothelial P-selectin expression and platelet activating factor release, which participate to induce early neutrophil adhesion and activation. We employed HUVEC and now show that thrombin induces the production of the chemokine IL-8 in a time- and dose-dependent fashion. Similarly, thrombin induced E-selectin expression on HUVEC. Both IL-8 secretion and E-selectin expression were preceded by an increase in steady state levels of the respective mRNAs. Thrombin action on HUVEC was inhibited by the specific thrombin inhibitor, hirudin. In addition, these effects of thrombin on HUVEC were mimicked by the 14-amino acid thrombin receptor agonist peptide, which triggers the native thrombin receptor in a similar fashion to thrombin itself. Although IL-1 and TNF-alpha also induce IL-8 and E-selectin, the thrombin effects in these experiments were not mediated by those cytokines, since neither IL-1 receptor antagonist nor anti-TNF-alpha Ab inhibited the effects of thrombin. Furthermore, IL-1alpha, IL-1beta, and TNF-alpha were not detected in the supernatants of thrombin-activated HUVEC. Although intracellular IL-1alpha was found in thrombin-activated HUVEC, antisense IL-1alpha had no inhibitory effect on IL-8 secretion. These results demonstrate that in addition to short term endothelial activation, thrombin also functions as a long acting proinflammatory agent by inducing endothelial synthesis of the mediators required for neutrophils activation and extravazation during inflammation.
...
PMID:Thrombin induces endothelial type II activation in vitro: IL-1 and TNF-alpha-independent IL-8 secretion and E-selectin expression. 916 65

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
...
PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

The characteristics of endothelin (ET) release from guinea-pig tracheal epithelium were investigated, including examination of the effects of several pro-inflammatory mediators. In confluent cultured guinea-pig tracheal epithelial cells (GPTECs) there was a time-dependent basal release of immunoreactive ET (ir-ET) from 4-48 h. Basal ir-ET release from GPTECs was unaffected by the peptidase inhibitors, thiorphan (10 microM), benzamidine (1 mM), pepstatin-A (30 microM), aprotinin (1 microgram/ml), bacitracin (20 micrograms/ml) or leupetin (50 microM), but was inhibited by phosphoramidon, the neutral metalloprotease inhibitor (IC50 = 16.8 microM), or the calcium chelator, EGTA (10 mM). There was little ir-ET release 1 day after placing GPTECs in culture, although appreciable release (> 10-fold higher) was detected on days 5 and 7. No significant release of ir-ET was demonstrated from intact guinea-pig trachea. Human thrombin (0.1-10 U/ml), LPS (0.3-10 ng/ml) and the phorbol ester, phorbol 12-myristate-13-acetate (0.1 nM-1 microM), significantly increased ir-ET release, whereas TNF-alpha (0.1-10 ng/ml), RANTES (0.1-100 nM), IL-1 (0.01-10 ng/ml), bradykinin (1 nM-10 microM), CGRP (0.01 nM-1 microM), PDGF (0.1-3 ng/ml), Sar9, Met(O2)11-Sub P, Nle10-NKA 4-10 and senktide (selective NK-1, NK-2 and NK-3 receptor agonists, respectively; 1 nM-10 microM), LTD4 (1 nM-10 microM) or major basic protein (10 nM-1 microM) were without stimulatory effect. The results indicate that the enzyme responsible for the basal release of ET from cultured GPTECs is a Ca(2+)-dependent, phosphoramidon-sensitive, neutral metalloprotease. Furthermore, normally there is minimal ET release from guinea-pig airway epithelium but this can be increased markedly by culturing the cells to confluence, and by select pro-inflammatory mediators.
...
PMID:Characterization of endothelin release from guinea-pig tracheal epithelium: influence of proinflammatory mediators including major basic protein. 969 42

The protein C/protein S anticoagulant pathway has been proposed to be a common link between coagulation and inflammation. Studies have suggested that a component of the anticoagulant pathway, activated protein C (APC), may play a role in the inflammatory response by modulating the effects of cytokines such as TNF and by blocking neutrophil activation. Cytokines are known to be intimately involved in the inflammatory response and to function in part to restore hemostatic balance. To begin to delineate what role APC may have in the inflammatory response, we have investigated the effect of APC on the production of the proinflammatory cytokines IL-6 and IL-8 in primary HUVEC, human microvascular endothelial cells, and human coronary artery endothelial cells. Our results have demonstrated that physiologic concentrations of APC significantly up-regulated the production of both IL-6 and IL-8. This increase, which was seen at both the RNA and protein level, was not due to either thrombin or LPS contamination of the APC preparation. Additional studies also showed that the APC-mediated up-regulation of IL-6 and IL-8 was IL-1 independent. Although neither purified protein C nor protein S alone had an effect on cytokine production, protein S, the cofactor for APC, significantly enhanced the ability of APC to up-regulate IL-6/IL-8 production. These results provide further evidence for a role for APC in the inflammatory response.
...
PMID:The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. 972 57

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.
...
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.
...
PMID:Synergistic interactions of bradykinin, thrombin, interleukin 1 and tumor necrosis factor on prostanoid biosynthesis in human periodontal-ligament cells. 983

To determine in vivo effects of interleukin (IL)-12 on host inflammatory mediator systems, 4 healthy chimpanzees received recombinant human IL-12 (1 microg/kg) by intravenous injection. IL-12 induced increases in plasma concentrations of IL-15, IL-18, and interferon-gamma (IFN-gamma), plus a marked antiinflammatory cytokine response (IL-10, soluble tumor necrosis factor [TNF] receptors, IL-1 receptor antagonist) and secretion of alpha-chemokines (IL-8, IFN-gamma-inducible protein 10) and beta-chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta). In addition, IL-12 elicited neutrophilic leukocytosis, neutrophil degranulation (elastase-alpha1-antitrypsin complexes), coagulation activation (F1 + 2 prothrombin fragment, thrombin-antithrombin III complexes), and fibrinolytic activation (tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes). IL-12-induced activation of multiple host mediator systems was found only after 8-24 h, remained detectable until the end of the 48-h observation period, and occurred in the absence of detectable TNF and IL-1beta. These data may contribute to understanding the role of IL-12 in the pathogenesis of sepsis syndrome and the toxicity found after repeated injections of IL-12.
...
PMID:Interleukin-12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees. 995 71

The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma. PPAR-alpha activation mediates pleiotropic effects such as stimulation of lipid oxidation, alteration in lipoprotein metabolism and inhibition of vascular inflammation. PPAR-alpha activators increase hepatic uptake and the esterification of free fatty acids by stimulating the fatty acid transport protein and acyl-CoA synthetase expression. In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II. PPARs are also expressed in atherosclerotic lesions. PPAR-alpha is present in endothelial and smooth muscle cells, monocytes and monocyte-derived macrophages. It inhibits inducible nitric oxide synthase in macrophages and prevents the IL-1-induced expression of IL-6 and cyclooxygenase-2, as well as thrombin-induced endothelin-1 expression, as a result of a negative transcriptional regulation of the nuclear factor-kappa B and activator protein-1 signalling pathways. PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity. Therefore, the pleiotropic effects of PPAR-alpha activators on the plasma lipid profile and vascular wall inflammation certainly participate in the inhibition of atherosclerosis development observed in angiographically documented intervention trials with fibrates.
...
PMID:Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. 1043 61


<< Previous 1 2 3 4 5 6 7 8 Next >>

---