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)

Human recombinant interleukin 1 alpha (IL-1 alpha) and IL-1 beta stimulated prostaglandin E2 synthesis in 3T3 fibroblasts in a time- and concentration-dependent manner. Enhanced prostaglandin E2 synthesis after IL-1 treatment was apparent by 1 hr and continued to increase for at least 2 days. Half-maximal stimulation occurred at 0.5 pM IL-1 alpha or IL-1 beta, and both interleukins were equally effective, with maximal stimulation occurring in response to 5-10 pM IL-1. In contrast to IL-1, bradykinin stimulation of prostaglandin E2 synthesis is rapid; its effect is maximal by 5 min. In cells that had been pretreated with IL-1 for 24 hr, prostaglandin E2 synthesis in response to bradykinin was amplified more than 10-fold. IL-1 also amplified the receptor-mediated formation of prostaglandin E2 by bombesin and thrombin. The lymphokine did not affect bradykinin receptor number or affinity. IL-1 treatment induced phospholipase A2 and cyclooxygenase but not phospholipase C or prostaglandin E isomerase. It also enhanced bradykinin-stimulated GTPase activity, suggesting possible induction of the GTP-binding regulatory protein coupled to the bradykinin receptor. Thus, IL-1 enhanced receptor-mediated release of prostaglandin E2 in response to bradykinin, bombesin, and thrombin by increasing the cellular levels of phospholipase A2, cyclooxygenase, and GTP-binding regulatory protein(s).
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PMID:Interleukin 1 amplifies receptor-mediated activation of phospholipase A2 in 3T3 fibroblasts. 290 Oct 97

Thrombin, besides being a potent coagulation factor, exerts influence on endothelial and leukocyte functions and may thus be involved in the regulation of inflammatory reactions. The present study investigated whether thrombin stimulates the production of growth-related cytokine/melanoma growth-stimulatory activity (GRO alpha/MGSA) in endothelial cells. Human umbilical vein endothelial cells (HUVEC) stimulated with thrombin were found to product GRO alpha/MGSA in a dose- and time-dependent manner. This action of thrombin was completely suppressed by preincubation with either hirudin or antithrombin-III (AT-III)-heparin. Interestingly, the thrombin receptor-activating peptide SFLLRN mimicked the action of thrombin. In addition, staurosporine, a protein kinase C (PKC) inhibitor, attenuated the production of GRO alpha/MGSA by thrombin, SFLLRN and phorbol 12-myristate 13-acetate (PMA), but left the action of interleukin-1 beta (IL-1 beta) unchanged. These results suggest that catalytic activation of thrombin receptor by thrombin results in GRO alpha/MGSA production, at least in part, via a pathway involving PKC in HUVEC.
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PMID:Thrombin induces GRO alpha/MGSA production in human umbilical vein endothelial cells. 748 42

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

Activated platelets have been shown previously to exhibit membrane-bound IL-1 bioactivity, which leads to the question of localization of the cytokine in platelets. Using immunocytological and flow cytometric techniques, we found IL-1 alpha and IL-1 beta in the cytoplasma of both resting and thrombin-activated platelets. Immunogold-silver staining of the cell surface of activated platelets as well as preembedding antibody treatment of platelets revealed the presence of IL-1 (alpha and beta) in low density on the surface of intact cells in contrast to distinct enrichment in the cytoplasma of damaged platelets. Fibrin fibres present between cells indicated adsorbance of IL-1. There was also weak binding of anti-IL-1 alpha to the surface of thrombin-activated platelets as shown by flow cytometry. Following activation there appears to be some transfer of IL-1 onto the cell surface of activated cells, the bulk of the cytokine, however, is probably not released prior to platelet disintegration. In summary, we present evidence for the presence of both IL-1 alpha and IL-1 beta in resting and activated platelets without being able to demonstrate localization of the cytokines to specific subcellular structures.
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PMID:Platelets contain interleukin-1 alpha and beta which are detectable on the cell surface after activation. 763 Nov 54

Some disorders of the central nervous system, such as trauma, meningitis, or subarachnoid hemorrhage (SAH), result in inflammation and fibrosis of the arachnoid membranes followed by hydrocephalus. To clarify the role of growth factors in the pathophysiology of arachnoid fibrosis, we investigated the response of leptomeningeal (LM) cells to growth factors elevated in the cerebrospinal fluid (CSF) of patients with subarachnoidal inflammation. We examined the proliferative responses of LM cells to thrombin, transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), acidic fibroblast growth factor (aFGF), platelet derived growth factor (PDGF), tumor necrosis factor-beta (TNF-beta) and interleukin 1-beta (IL1-beta). Thrombin, TGF-beta, EGF, aFGF and PDGF promoted LM cell proliferation. TGF-beta enhanced the proliferative effect of thrombin and EGF on LM cells. These findings suggest that thrombin and TGF-beta, which may be elevated in CSF following SAH, may cause subarachnoid fibrosis and subsequent hydrocephalus.
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PMID:Thrombin and TGF-beta promote human leptomeningeal cell proliferation in vitro. 764 16

Experiments were designed to examine whether thrombin affects the production of nitric oxide-like factor(s) evoked by interleukin-1 beta (IL-1 beta) in cultured smooth muscle cells from the rat aorta. IL-1 beta stimulated the release of nitrite (a stable oxidation product of nitric oxide) from cultured smooth muscle cells. Thrombin inhibited in a concentration-dependent manner the release of nitrite caused by IL-1 beta. The inhibition was prevented by hirudin (a thrombin inhibitor) and required the presence of thrombin before or during the induction period. Under bioassay conditions, the perfusates from columns containing IL-1 beta-treated smooth muscle cells relaxed detector rat aortic rings without endothelium. The addition of IL-1 beta-treated smooth muscle cells to suspensions of indomethacin-treated platelets inhibited their aggregation. Control untreated smooth muscle cells or cells treated with thrombin alone did not have such effects. The treatment of smooth muscle cells with IL-1 beta in combination with thrombin blunted both the relaxing activities of the perfusates under bioassay conditions and the inhibition of platelet aggregation. These observations indicate that thrombin inhibits the production of nitric oxide-like factor(s) evoked by the inducible nitric oxide synthase in cultured smooth muscle cells from rat aorta.
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PMID:Thrombin inhibits induction of nitric oxide synthase in vascular smooth muscle cells. 768 May 40

An expression vector bearing the gene segment encoding the mature form of ovine interleukin-1 beta (OvIL-1 beta) was constructed. This vector provided a rapid method for obtaining Escherichia coli derived recombinant OvIL-1 beta (rOvIL-1 beta) using the expression plasmid pGEX-2T. The level of expression of fusion protein in the soluble fraction was approximately 20% of the total accumulated proteins. Affinity purification by glutathione-Sepharose yielded a fusion protein and subsequent thrombin cleavage of this material yielded rOvIL-1 beta. The specific activity of the purified recombinant protein was 10(3)-10(4) times higher than the fusion protein. The rOvIL-1 beta was 10-100 times more potent than human interleukin-1 beta (HuIL-1 beta) in an ovine thymocyte proliferation assay, although they were of equal potency in the NOB-1/CTLL assay. This simple purification method, which produces purified rOvIL-1 beta with a high specific activity (approximately 10(8) U mg-1), will now make it possible to evaluate the in vivo effects of IL-1 beta in sheep.
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PMID:Expression and purification of recombinant ovine interleukin-1 beta from Escherichia coli. 794 6

We have investigated the role of platelets in regulating the hemostatic and vasomotor properties of vascular smooth muscle. Experiments were performed to examine the effect of the releasate from activated platelets on the production of nitric oxide from interleukin-1 beta (IL-1 beta)-treated cultured rat aortic smooth muscle cells. Treatment of vascular smooth muscle cells with IL-1 beta resulted in significant accumulation of nitrite in the culture media and in marked elevation of intracellular cyclic guanosine monophosphate (GMP) levels. The releasate from collagen-aggregated platelets blocked the IL-1 beta-mediated production of nitrite and the accumulation of cyclic GMP in smooth muscle cells in a platelet number-dependent manner. In functional assays, the perfusates from columns containing IL-1 beta-treated smooth muscle cells relaxed detector blood vessels without endothelium and the addition of IL-1 beta-treated smooth muscle cells to suspensions of platelets inhibited their thrombin-induced aggregation. The simultaneous treatment of smooth muscle cells with IL-1 beta and the platelet releasate abolished both the vasorelaxing activities of the perfusates and the inhibition of platelet aggregation. Platelet releasates treated with a neutralizing antibody to platelet-derived growth factor (PDGF) failed to block IL-1 beta-induced nitric oxide production by the smooth muscle cells, as measured by both biochemical and functional assays. The platelet releasate from a patient with gray platelet syndrome likewise failed to block IL-1 beta-induced nitrite release by smooth muscle cells. These results demonstrate that platelets downregulate the production of nitric oxide by IL-1 beta-treated vascular smooth muscle cells through the release of PDGF. This effect may represent a novel mechanism by which platelets regulate vasomotor tone and thrombus formation at sites of vascular injury.
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PMID:Platelets inhibit the induction of nitric oxide synthesis by interleukin-1 beta in vascular smooth muscle cells. 814 51

We investigated the effect of blood mononuclear cell-conditioned medium on prostacyclin (PGI2) production by human umbilical vein endothelial cells in culture (HUVEC), and compared the potency of the conditioned medium in PGI2 production with that of various cytokines and lipopolysaccharide (LPS). HUVEC which had been preincubated with LPS, interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor (TNF alpha), or interferon-gamma (IFN-gamma) produced more PGI2 than control cells in response to thrombin. However, the HUVEC preincubated with the conditioned medium made with mononuclear cells with or without LPS (LPS-Mo-CM, Mo-CM) produced more PGI2 than those preincubated with LPS, IL-1 alpha, IL-1 beta, TNF alpha, or IFN-gamma. Although the concentrations or IL-1 beta and TNF alpha in the post-culture medium of HUVEC treated with LPS-Mo-CM were much higher than those with Mo-CM, LPS-Mo-CM which was made with 13,000/ml of mononuclear cells and 1 microgram/ml of LPS did not significantly augment the subsequent PGI2 production by HUVEC as compared with Mo-CM made with the same numbers of mononuclear cells. PGI2 production by Mo-CM-treated HUVEC still exceeded that of control cells, even when an excess amount of antibody to TNF alpha and/or IL-1 alpha was added to the Mo-CM. It is possible that Mo-CM contains unknown cytokines besides IL-1 and TNF which stimulate the HUVEC to produce PGI2.
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PMID:Mononuclear cell-conditioned medium enhances thrombin-stimulated PGI2 production by human umbilical vein endothelial cells in culture. 824 72

Lipoxin A4 (LXA4), but not lipoxin B4, induced in vitro a dose-dependent, slowly emerging hyperadhesiveness in human umbilical vein endothelial cells (HUVEC), leading to a 1.9-fold increase in the binding of neutrophils (polymorphonuclear neutrophil granulocytes [PMN]). The maximal response to LXA4 occurred at 1 nmol/L and after 30 minutes of treatment of HUVEC. These response kinetics were intermediate in comparison with those of fast-acting inducers of HUVEC adhesivity (eg, thrombin, leukotriene B4 [LTB4] or platelet activating factor [PAF]), needing 5 to 15 minutes, or to the slow inducer interleukin-1 (IL-1 beta), which requires hours. The maximal LXA4 effect was slightly lower than that of LTB4 (100 nmol/L) and thrombin (1 U/mL), and less than that of PAF (100 nmol/L) or IL-1 beta (2.5 U/mL) (2.2-, 2.0-, 2.4-, or 13.6-fold increases, respectively). The LXA4 effect was inhibited by the PAF receptor antagonist WEB-2086; however, it could not be blocked by pertussis toxin. LXA4 conferred a slow, sustained increase in HUVEC cytosolic calcium ion concentrations, whereas thrombin did so rapidly and transiently. LXA4 also caused PMN to become hyperadhesive. Thus, this novel effect of LXA4 on HUVEC appears to be associated with endogenous PAF expression and slow increases of cytosolic calcium concentrations but not pertussis-sensitive G proteins.
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PMID:Lipoxin A4 induces hyperadhesiveness in human endothelial cells for neutrophils. 839 56


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