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:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this phase I study was to evaluate the toxicity and biological activity of autologous blood-derived macrophages activated ex-vivo with recombinant human interferon gamma (rhuIFN gamma) [monokine-activated killer (MAK) cells] and administered intravenously to 11 lung cancer patients once a week for 6 consecutive weeks. Peripheral blood monocytes were collected by leukapheresis and then purified by counterflow elutriation. The MAK cells were generated by culturing the purified monocytes in Teflon bags for 7 days and adding rhuIFN gamma to the cultured cells for the last 18 h. These MAK cells expressed differentiation-associated surface antigen MAX1, and were cytotoxic in vitro against tumour cell line U937. The MAK cells were infused at dose levels from 1 x 10(7) to 5 x 10(8) on an intrapatient dose-escalating schedule. No severe adverse side-effects occurred. Toxicity was mild to moderate [primarly fever (75%) and chills (32%)], non-dose-dependent, and non-cumulative. No consistent change in haemostatic function, or liver or renal function was observed. Dose-limiting toxicity was not reached at 5 x 10(8) cells (optimal dose reproduced for each patient). The maximum tolerated dose was not determined. The immunomodulatory activity of i.v. infused MAK cells was demonstrated both in vivo by significant increases in granulocyte count and neopterin level in the patients' peripheral blood post-infusion and in vitro by secretory products (IL-1. TNF alpha, neopterin, and thromboplastin-like substance) in the culture supernatants. The in vivo traffic patterns of autologous MAK cells labelled ex-vivo with 111In oxine were studied in 7 patients. Gamma imaging showed an immediate but transient lung uptake (less than 24 h), and a progressive uptake of radioactivity in the liver and spleen was seen from 6 h to 72 h post-infusion. Our results indicate that the preparation of high numbers of autologous, blood-derived MAK cells is a feasible procedure, and their transfusion is safe for patients. This immunotherapeutic approach seems to be encouraging from the point of view of establishing an adjuvant therapeutic modality in cancer patients with minimal residual disease.
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PMID:Phase I trial of intravenous infusion of ex-vivo-activated autologous blood-derived macrophages in patients with non-small-cell lung cancer: toxicity and immunomodulatory effects. 165 Nov 60

Macrophages were harvested from home cage control (HCC) mice, and from mice which had been stressed by repeated brief exposures (3-8 min) to cold water at 10-15 degrees C twice daily for 8 or 14 days. Macrophages obtained from mice stressed 8 or 14 days compared to macrophages from HCC mice showed in vitro increased amounts of membrane-bound prothrombinase activity, whereas the thrombin degradation activity was unchanged. Furthermore, macrophages of mice stressed 8 days showed increased release of coagulation factor X/Xa to supernatant in vitro. These findings suggest an increased amount of prothrombinase complex enzymes on the surface of macrophages from mice stressed 8 days, and increased activity of the prothrombinase enzyme in macrophages from mice stressed 14 days. The synthesis of proteoglycans (PG) and glycosaminoglycans (GAG) was increased in macrophages from mice stressed 8 days compared to macrophages from HCC mice and mice stressed 14 days. When macrophages from mice stressed 8 days or HCC mice were stimulated in vitro with phorbol myristate acetate (PMA) and IL-1 or PMA and IL-2, a changed PG/GAG synthesis was observed only in macrophages from the HCC animals. Furthermore, both the tumour cytotoxicity and the released tumour necrosis factor (TNF) were decreased from macrophages from mice stressed 14 days compared to HCC mice. The results suggest that the macrophages of stressed mice have an altered mode of function more complex than a simple general suppression or activation.
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PMID:The effect of stress in vivo on the function of mouse macrophages in vitro. 204 61

Fibrin deposition is an important histopathologic feature of inflammation and is mediated, in part, by monocyte/macrophage procoagulants. rIFN gamma acted in synergy with suboptimal levels of bacterial LPS by priming thioglycollate-induced mouse peritoneal exudate cells (TG-PEC) to express high levels of surface procoagulant. TFN-alpha beta, TFN-alpha, IL-1, either alone or in combination with LPS or IFN-gamma, had no effect on macrophage procoagulant activity expression. In contrast to the dramatic increases of macrophage procoagulant activity induced by IFN-gamma/LPS, on exudate macrophages, normal peritoneal macrophages, or peripheral blood monocytes were unresponsive suggesting that the state of activation of the macrophage determines reactivity. IFN-gamma induced a Factor VIIa-like activity detected only after cell disruption. Synergy between LPS and IFN-gamma-induced procoagulants may occur as the result of the assembly of the thromboplastin (induced by LPS), Factor VII/VIIa complex on the macrophage surface. RNA synthesis was required for procoagulant induction. Procoagulant expression may, as for other cytokines involved in inflammatory responses, be regulated by short lived repressor proteins as low dose cycloheximide superinduced procoagulant responses to both LPS and IFN-gamma and caused the extracellular expression of procoagulant in response to IFN-gamma. This study suggests an important role for IFN-gamma in the assembly of components of the extrinsic coagulant cascade on the macrophage surface. The synergy between IFN-gamma and LPS may moderate macrophage-initiated fibrin deposition characteristic of inflammatory responses.
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PMID:Recombinant IFN-gamma synergizes with lipopolysaccharide to induce macrophage membrane procoagulants. 245 19

IL-1, IL-2, and TNF alpha are important biological response modifiers of inflammatory and immunological reactions. Our experiments show that these cytokines are potent inducers of thromboplastin (TPL) activity but that their effects differ with regard to cell type and kinetics in human umbilical vein endothelial cells (HUVEC), monocytes (M), and mononuclear blood cells (MNC). Recombinant IL-1 alpha, rIL-1 beta and rTNF alpha all induced a dose-dependent increase in endothelial cell TPL activity, whereas rIL-2 had essentially no such effect. In the case of M and MNC cultures, IL-1 and IL-2 each induced TPL synthesis, IL-2 somewhat more slowly than IL-1. Special care was taken to exclude the effect of endotoxin present in the IL-1 preparations. Recombinant TNF alpha had a markedly smaller or no effect. When LPS was used to induce TPL synthesis, addition of rTNF alpha further enhanced HUVEC TPL, whereas no effect or a decrease in TPL was seen in MNC and M, especially in the presence of CsA and TNF alpha. Recombinant IL-1 beta also induced the synthesis of clotting factor VII in monocytes, thus allowing the formation of TPL-factor VII complexes, a most powerful trigger of blood clotting. IL-1 alpha, IL-2, and TNF alpha had no effect on the level of factor VII activity. Cyclosporine significantly augmented the level of TPL activity in HUVEC stimulated with rIL-1 alpha, rIL-1 beta, and rTNF alpha and in MNC and M stimulated with rIL-1 alpha, rIL-1 beta, and rIL-2. These actions of cytokines and cyclosporine may contribute significantly to the development of thrombotic reactions and fibrin deposits in transplanted organs, as well as to other pathophysiological pathways where activated clotting factors are involved.
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PMID:Cytokine-induced procoagulant activity in monocytes and endothelial cells. Further enhancement by cyclosporine. 305 64

Monocytes and macrophages respond to a number of exogenous agents by alterations in metabolism and gene expression in a process loosely called 'activation'. The question arises whether these alterations in cellular activity are the pleiotropic effects of one programmed activation process or result from separately programmed activation pathways. We report that certain cytokines (interleukin 1 (IL-1 alpha, IL-1 beta) and interleukin 2 (IL-2] which all activate monocytes, induce the synthesis of thromboplastin (TPL) and (IL-1 beta only) factor VII. Interferon-gamma (IFN-gamma) and tumour necrosis factor alpha (TNF alpha) do not induce monocyte procoagulant activity, although they both activate monocytes in several respects. Our data thus show that different states of activation are induced. Similar observations have been made by others using different systems.
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PMID:Activation of monocytes--more than one process. Differential effect of cytokines on monocytes. 312 78

Induction of monocyte/macrophage procoagulants may occur as the result of activation of the cell-mediated immune (CMI) response. Macrophage procoagulant inducing factor (MPIF), a soluble product of stimulated TDTH lymphocytes, may act together with two monokines, interleukin 1 and tumour necrosis factor alpha, which induce thromboplastin on endothelial cells, to initiate the fibrin deposition which is a common feature of many diseases in which CMI plays a role. Murine MPIF is chemically distinct from a number of other well characterized lymphokines in that the two major activities, MPIF alpha and MPIF beta are heparin-binding proteins with high isoelectric points. Fractions highly enriched for MPIF induced interstitial fibrin deposition when injected intradermally. In addition, intense infiltration of polymorphonuclear leucocytes (PWN) and mononuclear cells was seen 4-24 h following intradermal injection. In vitro experiments have confirmed that this lymphokine is a potent chemotactic agent for these cells. These results suggest that MPIF plays a central role in the expression of histopathological features of delayed-type hypersensitivity reactions. Monocyte and macrophage procoagulants induced by MPIF would contribute significantly to the activation of coagulation which not only results in fibrin deposition but also in the production of activated serine proteases and fibrinopeptides which may potentiate an inflammatory response.
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PMID:Coagulation and the expression of cell-mediated immunity. 330 39

Familial Mediterranean Fever (FMF) is an inherited disease of unknown etiology characterized by recurrent inflammatory episodes. Circulating fibrin was found in patients with FMF in absence of clinical manifestation of thrombosis and was statistically less frequently observed in patients treated with colchicine. These results suggest a cellular dysfunction. Therefore, we examined the procoagulant activity (PCA) of isolated mononuclear leukocytes and purified monocytes from FMF patients (n = 20). No PCA was detectable on freshly-isolated monocytes. After several hours of culture. FMF monocytes contained more PCA than control cells and the difference was more marked after endotoxin stimulation. Data obtained with coagulation factor-deficient plasma and anti-human apoprotein III antiserum indicated that the enhanced PCA in FMF monocytes is thromboplastin-like. Lysozyme and interleukin 1 production by monocytes were similar in patients and controls. The increased monocyte PCA appears to be due to an intrinsic and selective higher responsiveness of monocytes.
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PMID:Increased procoagulant response of monocytes from patients with familial Mediterranean fever. 381 May 56

The conversion of protein C into activated protein C (APC) by the thrombin-thrombomodulin complex on the surface of endothelial cells initiates an essential negative feedback reaction on blood coagulation. APC, together with its non-enzymic cofactor protein S, inactivates factors Va and VIIIa, the non-enzymic protein cofactors of the prothrombinase and intrinsic tenase complex, by proteolytic degradation. In this study we report that prothrombin activation products, generated by the prothrombinase complex on the surface of quiescent endothelial cells, are able to activate protein C. Subsequent inactivation of factor Va by the APC that was formed decreased the rate of prothrombin activation, thus demonstrating in vitro the negative feedback loop on coagulation factor activation. The anticoagulant feedback reaction of APC on the prothrombinase complex was stimulated 3-4-fold by the addition of protein S but not by thrombin-cleaved protein S or by protein S complexed with C4b-binding protein. Stimulation of endothelial cells with 50 pM tumour necrosis factor (TNF) or 500 pM interleukin 1 (IL-1) resulted in a 70% decrease in activation of protein C by exogenously added alpha-thrombin, which seemed to be due to down-regulation of thrombomodulin activity on the surface of endothelial cells. However, when prothrombin activation products generated in situ were allowed to activate protein C, stimulation of endothelial cells with TNF and IL-1 resulted in only a 25% decrease in activation of protein C. Stimulation with TNF or IL-1 did not affect the ability of endothelial cells to support prothrombinase activity. We investigated whether the differences in extent of protein C activation by exogenously added alpha-thrombin and by prothrombin activation products generated in situ were due to meizothrombin formed during prothrombin activation. Previous reports from our groups revealed that meizothrombin is generated as a transient intermediate during prothrombin activation on phospholipid vesicles and endothelial cells. Here we show that meizothrombin is at least a 6-fold better activator of protein C on the surface of endothelial cells than is alpha-thrombin. These results demonstrate that meizothrombin, formed during the initial phase of prothrombin activation, efficiently down-regulates both its own formation and that of thrombin.
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PMID:Protein C activation on endothelial cells by prothrombin activation products generated in situ: meizothrombin is a better protein C activator than alpha-thrombin. 891 73

Ribavirin, a synthetic guanosine analogue, possesses a broad spectrum of activity against DNA and RNA viruses. It has been previously shown to attenuate the course of fulminant hepatitis in mice produced by murine hepatitis virus strain 3. We therefore studied the effects of ribavirin on murine hepatitis virus strain 3 replication, macrophage production of proinflammatory mediators including TNF, IL-1, and the procoagulant activity (PCA), fgl2 prothrombinase; and Th1/Th2 cytokine production. Although ribavirin had inhibitory effects on viral replication (<1 log), even at high concentrations complete eradication of the virus was not seen. In contrast, at physiologic concentrations (up to 500 microg/ml), ribavirin markedly reduced viral-induced parameters of macrophage activation. With ribavirin treatment, the concentrations of PCA, TNF-alpha and IL-1beta all decreased to basal concentrations: PCA from 941 +/- 80 to 34 +/- 11 mU/10(6) cells; TNF-alpha from 10.73 +/- 2.15 to 2.74 +/- 0.93 ng/ml; and IL-1beta from 155.91 +/- 22.62 to 5.74 +/- 0.70 pg/ml. The inhibitory effects of ribavirin were at the level of gene transcription as evidenced by Northern analysis. Both in vitro and in vivo, ribavirin inhibited the production of IL-4 by Th2 cells, whereas it did not diminish the production of IFN-gamma in Th1 cells. In contrast, ribavirin had no inhibitory effect on TNF-alpha and IL-1beta production in LPS-stimulated macrophages. These results suggest that the beneficial effects of ribavirin are mediated by inhibition of induction of macrophage proinflammatory cytokines and Th2 cytokines while preserving Th1 cytokines.
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PMID:Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. 953 10

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


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