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)

Expression of tumor necrosis factor (TNF alpha), tissue factor (TF), and interleukin 1-beta (IL-1 beta) mRNA was evaluated in monocytes isolated from patients infected with human immunodeficiency virus (HIV). There was a significant depression (66%) of the induced level of TF mRNA expression in response to lipopolysaccharide. Conversely, the response of TNF alpha and IL-1 beta, following LPS induction, was "normal." TF mRNA reduction was also observed to a lesser degree in AIDS-related complex patients (20%) but not in asymptomatic seropositives. TF is necessary for initiation of the coagulation protease cascade, leading to thrombin production and fibrin deposition, which play a role in inflammatory responses. Its selective reduction may be a factor in the diminished resistance to secondary infections observed in AIDS. Further, since the TF defect increases as patients progress toward AIDS, it may serve as a marker for disease progression.
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PMID:A selective defect in tissue factor mRNA expression in monocytes from AIDS patients. 229 2

Previous studies have indicated that activation of endothelial cells may lead to the production of tissue factor. We have studied the effect of endothelial cell activation and subsequent tissue factor synthesis on thrombus formation on the extracellular matrix in flowing blood. Endothelial cells were stimulated with tumor necrosis factor, endotoxin, or phorbol ester. Coverslips with activated cells or their extracellular matrix were introduced into a perfusion system and exposed to blood anticoagulated with 20 U/ml low molecular weight heparin. This concentration allowed manipulation of blood without activation of the coagulation cascade. Platelet deposition and fibrin formation were evaluated by morphometry, and fibrinopeptide A formation was assayed as a measure of thrombin generation. Activation of endothelial cells caused fibrinopeptide A generation in the perfusate and some deposition of fibrin on endothelial cells; however, platelets were not deposited. The matrix of the stimulated endothelium also caused enhanced fibrinopeptide A generation, and platelet aggregates and fibrin were deposited on the matrix. Maximal effects were observed with stimulation periods between 4 and 10 hours and were still clearly present after 18 hours. Increase in shear rate, perfusion time, and platelet number resulted in an increase in platelet adhesion, but platelet aggregate formation as a percentage of adhesion remained constant. Platelet aggregate formation and fibrinopeptide A generation were inhibited with antibodies against tissue factor or factor VIIa. Platelet aggregate formation alone was inhibited by antibodies against glycoprotein IIb/IIIa. Polymerization of fibrin on the matrix was best supported in perfusions at a low shear rate. The new in vitro thrombosis model presented here provides a powerful tool for study of the regulation of thrombogeneity by the vessel wall in response to various stimuli.
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PMID:Activation of endothelial cells induces platelet thrombus formation on their matrix. Studies of new in vitro thrombosis model with low molecular weight heparin as anticoagulant. 229 47

The human alveolar macrophage product, enzyme-releasing peptide (ERP), has a molecular mass of 8,000 Da, and releases azurophilic and specific granule constituents from neutrophils. A murine monoclonal anti-ERP antibody (12E10H), previously used to show a lack of antigenic identity between ERP and C5a, interleukin 1, tumor necrosis factor, and gamma-interferon, showed no cross-reactivity with interleukin 8. 12E10H and a fluorescein-labeled second antibody were used to visualize ERP on the macrophage surface. ERP was removed from alveolar macrophages by a 3-min incubation with 5 X 10(-7) M bovine pancreatic trypsin at 37 degrees C. The washed trypsinized cells could readhere to plastic and exclude trypan blue. Dilution of the trypsin-derived ERP released myeloperoxidase from cytochalasin-B-treated neutrophils dose dependently. The enzyme-releasing ability of the trypsin-derived material was removed by immunoprecipitation using antibody 12E10H bound to Staphylococcal protein A Sepharose 4B. The estimated molecular mass of the trypsin-derived ERP (by molecular sieve chromatography on HPLC) was approximately 8,500 Da. Other proteases (plasmin, thrombin, and cathepsin G) also released ERP from the cell surface, but the ERP was not an active secretagogue for neutrophils. However, macrophages cultured with protease inhibitors did not show decreased ERP accumulation in the medium. Our data indicate that ERP exists on the surface of human alveolar macrophages and can be released by proteases found within the lung environment in some disease states.
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PMID:Liberation of a neutrophil enzyme-releasing peptide from the surface of human alveolar macrophages. 236 Jun 46

Endothelin-1 (ET-1) has been identified in the conditioned medium of porcine endothelial cells. Human endothelin (ET-1) cloned from a placenta cDNA library is similar to porcine, but it is not known whether endothelin itself is secreted by human endothelial cells. To answer this question, a conditioned medium taken every 48 h from confluent cultures of umbilical vein endothelial cells was analyzed by HPLC and all fractions were tested for their ability to inhibit [125I]ET-1 binding on human placenta membranes. Only one fraction did inhibit [125I]ET-1 binding. When the conditioned medium was spiked with ET-1, the same single fraction inhibited [125I]ET-1 binding showing that ET-1, itself, is present in the conditioned medium of human endothelial cells. ET-1 accumulates with time, reaching a plateau at 48 h. ET-1 secretion is not increased by a 24-h incubation of endothelial cells with phorbol myristate acetate, interleukin-1, tumor necrosis factor, thrombin or neuropeptide Y.
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PMID:Human cultured endothelial cells do secrete endothelin-1. 247 22

Tumor necrosis factor stimulated prostaglandin E2 synthesis in Swiss 3T3 fibroblasts. Interleukin 1 also stimulated prostaglandin synthesis. Simultaneous addition of tumor necrosis factor and interleukin 1 synergistically stimulated prostaglandin synthesis, even when both growth factors were added at what would be supramaximal concentrations by themselves. Several small peptides and nonpeptides rapidly stimulate prostaglandin synthesis in these cells. Pretreatment with tumor necrosis factor synergistically enhanced prostaglandin synthesis in response to bradykinin, bombesin, thrombin, norepinephrine, and platelet-activating factor. Thus, tumor necrosis factor stimulates prostaglandin synthesis and greatly amplifies prostaglandin synthesis in response to other agonists. This finding may have significance in chronic inflammatory diseases such as rheumatoid arthritis in which several hormones and growth factors may synergistically augment eicosanoid synthesis.
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PMID:Tumor necrosis factor causes amplification of arachidonic acid metabolism in response to interleukin 1, bradykinin, and other agonists. 255 Apr 84

In this study we assessed the viability of cultured human umbilical vein endothelial cells (HUVE) treated with bacterial lipopolysaccharide (LPS), recombinant human interleukin-1 (rhIL-1), or recombinant human tumor necrosis factor-alpha (rhTNF-alpha) during inhibition of RNA or protein synthesis. Cytotoxicity was determined by 51Cr activity retained in labeled HUVE monolayers after exposure to LPS, rhIL-1 or rhTNF-alpha, and cycloheximide (Cx) or actinomycin D (Act D). Lipopolysaccharide (150 ng/ml), rhIL-1 (100 pg/ml), or rhTNF-alpha (20 ng/ml) alone was not toxic to HUVE in an 18-hr incubation. Cycloheximide alone (1 microgram/ml for 18 hr) or Act D alone (1 microgram/ml for 6 hr) was also not toxic to HUVE. However, coincubation of HUVE with Cx and LPS (150 ng/ml), rhIL-1 (10 pg/ml), or rhTNF-alpha (20 ng/ml) produced significant cytotoxicity at 18 hr (70 +/- 4% for LPS, 75 +/- 5% for rhIL-1, and 52 +/- 5% for rhTNF-alpha; mean +/- SEM of 18, 16, and 19 separate experiments, respectively). Similarly, coincubation of HUVE with Act D and LPS, rhIL-1, or rhTNF-alpha resulted in 82 +/- 5%, 85 +/- 3%, and 67 +/- 4% cytotoxicity, respectively, at 6 hr (mean +/- SEM of 5 separate experiments for LPS, and 7 separate experiments each for rhIL-1 and rhTNF-alpha). At the highest concentrations of LPS, rhIL-1, or rhTNF-alpha, cytotoxicity during coincubation with Cx or Act D was detected as early as 2 hr and was near maximal by 6 hr. In contrast to LPS, rhIL-1, or rhTNF-alpha, recombinant human interferon-gamma (up to 100 U/ml), or human alpha-thrombin (up to 10 U/ml), produced no cytotoxicity in the presence of Cx. Recombinant human lymphotoxin (up to 50 ng/ml) had a detectable cytotoxic effect in the presence of Cx although it was significantly less than that seen with rhTNF-alpha. Furthermore, coincubation of human fibroblasts and human smooth muscle cells with Cx and LPS, rhIL-1, or rhTNF-alpha produced no cytotoxicity. We conclude that under these culture conditions, LPS, rhIL-1, or rhTNF-alpha produces a lethal injury to HUVE when de novo RNA or protein synthesis is inhibited. These results suggest that LPS, rhIL-1, and rhTNF-alpha may act via a common pathway in endothelial cells and that protein synthesis is important in regulating the response to these stimuli.
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PMID:Human endothelial cell response to lipopolysaccharide, interleukin-1, and tumor necrosis factor is regulated by protein synthesis. 278 80

Components of the CDw18 leukocyte surface glycoprotein complex (Mo1/LFA-1/GP 150,95 or MAC-1, LFA-1 family) are required for some adhesion-related functions of human neutrophils (PMNs). We evaluated the ability of monoclonal antibodies (MoAb) directed against specific determinants on the CDw18 glycoproteins to inhibit neutrophil adherence to cultured human endothelial cells (EC) stimulated by a variety of agonists, including thrombin and leukotriene C4, which induce the EC-dependent adhesion of PMNs. MoAb 60.3, an antibody that binds to an epitope common to the 3 heterodimer subunits of the neutrophil CDw18 complex, potently inhibited (90-100%) the rapid (5-30 minute) adherence response stimulated by N-formyl-methyionyl-leucyl-phenylalanine, leukotriene B4, platelet-activating factor, phorbol myristate acetate, Ionophore A23187, and tumor necrosis factor. MoAbs directed against epitopes on the alpha polypeptide of the CD11b (Mol, MAC-1) heterodimer also inhibited PMN adherence to EC and to cell-free surfaces induced by these agonists. In contrast, the anti-CDw18 MoAbs had a trivial effect on maximal EC-dependent neutrophil adherence stimulated by thrombin and leukotriene C4, and incompletely inhibited PMN adherence induced by these agonists under submaximal conditions. These findings indicate that there is an alternative mechanism for neutrophil adherence, presumably resulting from molecular alterations of the EC surface, that does not require the PMN CDw18 glycoproteins. They also suggest that the inability to adhere to endothelium may not completely account for the defect in chemotaxis that is observed in vivo in neutrophils that are deficient in the CDw18 complex.
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PMID:Neutrophil adherence to human endothelium in vitro occurs by CDw18 (Mo1, MAC-1/LFA-1/GP 150,95) glycoprotein-dependent and -independent mechanisms. 282 29

A plasminogen activator inhibitor was purified to apparent homogeneity from conditioned media of U138 cells. The inhibitor is a glycoprotein with a pI of 5.4 and an apparent molecular weight of 45,000. The inhibitor forms sodium dodecyl sulfate-stable complexes with plasminogen activators and trypsin but not with plasmin, thrombin, or pancreatic kallikrein. Some biochemical and immunochemical characteristics of the U138 inhibitor distinguish it from other known plasminogen activator inhibitors. The expression of this inhibitor by U138 cells could be modulated by incubation in phorbol myristate acetate, interleukin-1, tumor necrosis factor, and gamma interferon, but not in beta interferon. Thus, the expression of the plasminogen activator inhibitor can be influenced by biological response modifiers known to be active in the brain and in the neural response to inflammatory stimuli. Therefore, this inhibitor, along with protease nexin, may be involved in brain development and regulation.
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PMID:Purification and partial characterization of a plasminogen activator inhibitor from the human glioblastoma, U138. 314 98

Ascitic fluid form ovarian cancer patients (n = 16), but not from patients with other cancers or with benign diseases, contains a growth-promoting activity which induces the proliferation of both fresh ovarian cancer cells (n = 5) and the ovarian cancer cell line HEY. The ascitic fluid growth factor(s) appears to signal cells through binding and activation of specific, saturable, high-affinity cell surface receptors. Incubation of fresh or cultured ovarian cancer cells with a partially purified preparation of ascitic fluid stimulates phosphatidylinositol turnover and increases cytosolic-free calcium. Each of these biochemical events has been implicated in the action of growth factors. Purified preparations of previously identified growth factors including epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, platelet-derived growth factor, thrombin, insulin, interleukin-1, interleukin-2, vasopressin, angiotensin, alpha- and gamma-interferons, and fibroblast growth factor did not increase cytosolic-free calcium in either fresh ovarian cancer cells or HEY cells. Therefore, ascitic fluid appears to contain one or more previously unidentified growth factors which activate ovarian cancer cells through phosphatidylinositol hydrolysis and resultant changes in cytosolic-free calcium.
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PMID:A putative new growth factor in ascitic fluid from ovarian cancer patients: identification, characterization, and mechanism of action. 342 89

Experiments were designed to examine whether or not insulin-like growth factor I (IGF-I), which is produced by vascular cells in response to injury, affects the production of nitric oxide evoked by the inducible nitric oxide synthase in cultures of smooth muscle cells from the rat aorta. Nitric oxide production was assessed indirectly by the measurement of nitrite accumulation and nitric oxide synthase activity by determining the formation of L-citrulline from L-arginine. Nitric oxide synthase was induced in vascular smooth muscle cells that had been exposed to interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha). IGF-I inhibited, in a concentration-dependent manner, the production of nitrite and L-citrulline evoked by IL-1 beta or TNF-alpha. The inhibition caused by IGF-I required the presence of the growth factor during the induction of nitric oxide synthase. Two IGF-I-related proteins, IGF-II and insulin, also inhibited, but to a smaller extent, the release of nitrite and the formation of L-citrulline stimulated by IL-1 beta. Under bioassay conditions, the perfusates from columns containing IL-1 beta-treated smooth muscle cells relaxed rings of rat aorta without endothelium that had been contracted with phenylephrine; these relaxations were reversed by nitro-L-arginine. Addition of IL-1 beta-treated vascular smooth muscle cells to indomethacin-treated platelets inhibited their aggregation to thrombin; methylene blue prevented this inhibition. Control smooth muscle cells or cells exposed to IGF-I alone did not have such effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-like growth factor I inhibits induction of nitric oxide synthase in vascular smooth muscle cells. 750 7


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