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:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 (IL-1) release from monocyte-macrophages (Mo) appears dependent on pericellular proteolysis mediated by plasmin. Thus plasminogen activator inhibitors (PAI) which bind the serine proteases responsible for the conversion of plasminogen to plasmin, may inhibit IL-1 release from Mo. We have examined the effect of purified PAI from a hepatoma cell line Hep G2, on IL-1 release from Mo with secondary effects on lymphocyte proliferation in vitro. Fast acting inhibitors of both urokinase (u-PA) and tissue plasminogen activator (two chain t-PA) were noted in harvest fluids of Hep G2 cells. These inhibitors were stable at pH 3 but lost activity at 45 degrees C. They were SDS-stable and migrated with Mr53 and 104 kDa. These properties conformed to characteristics of type-1 plasminogen activator inhibitor (PAI-1). Partially purified PAI-1 added to human Mo cultured on 125I fibrin layer both in the presence and absence of plasminogen inhibited secretion of IL-1 by Mo in response to LPS. This effect, however, did not correlate with the inhibition of plasminogen dependent fibrinolysis. This suggested a degree of sequestration and inaccessibility of membrane bound u-PA of LPS activated Mo to PAI-1. PAI-1, in addition, inhibited mitogen stimulated peripheral blood mononuclear cell (PBMC) proliferation at similar concentration ranges. This effect was abrogated by the addition of specific antisera to PAI-1. PAI-1 may be released as part of an acute phase response. In addition to influencing fibrinolysis, PAI-1 may constitute a negative feedback pathway on Mo IL-1 release and subsequent immune activation in vivo.
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PMID:Monocyte-macrophage release of IL-1 is inhibited by type-1 plasminogen activator inhibitors. 196 70

Mononuclear phagocytes regulate the generation of plasmin by secreting urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-2 (PAI-2). We investigated the production of plasminogen activator (PA) and PA inhibitor by the human monocytic leukemia cell line, THP-1. Similar to U937 monoblast-like cells and peripheral blood monocytes (PBM), THP-1 cells produce a PA that is specifically neutralized by anti-uPA antibody and comigrates with human high molecular mass uPA (54 kDa) on casein-plasminogen zymogaphy. PA activity could be dissociated from intact THP-1 cells by brief treatment with a weak acid-glycine buffer, indicating that the uPA is secreted and bound to receptors on the plasma membrane. Regulation of uPA proceeds normally in THP-1 cells, with cell-associated PA activity increasing from 77 +/- 20 to 163 +/- 26 and 325 +/- 30 mPU/10(6) cells in response to PMA and LPS, respectively; parallel increases in steady state levels of uPA mRNA were observed. In contrast to normal expression of uPA activity, functional PAI-2 could not be demonstrated in either the conditioned media or cell lysates of THP-1 under basal or stimulated conditions. Both U937 and PBM secrete low levels of PA inhibitor activity that increase substantially in response to stimulation with PMA and LPS. Immunoreactive PAI-2, measured by ELISA, was undetectable in THP-1 lysates or conditioned medium, but was consistently present in U937 and PBM, paralleling the presence of PA inhibitor activity. THP-1 cells express low levels of an abnormally sized mRNA for PAI-2 and demonstrate a regulatory defect whereby steady state levels of PAI-2 mRNA are markedly reduced upon stimulation with PMA or LPS. By contrast, U937 and PBM respond to identical stimulation with increases in PAI-2 mRNA. We conclude that THP-1 cells express a structurally abnormal species of PAI-2 mRNA, with complete loss of inhibitory activity as well as altered function of PMA- and LPS-responsive regulatory elements.
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PMID:The THP-1 cell line is a urokinase-secreting mononuclear phagocyte with a novel defect in the production of plasminogen activator inhibitor-2. 230 45

We have studied the activation state of the fibrinolytic system in 39 patients with systemic meningococcal disease (SMD). Patients defined as having fulminant septicemia (n = 13) with high (greater than 700 ng/L) levels of endotoxin (LPS) in plasma and severe coagulopathy, had significantly lower functional levels of plasminogen (P less than 0.05) and alpha-2-antiplasmin (P less than 0.01) and higher antigen levels of plasminogen activator inhibitor 1 (PAI-1) (P less than 0.01), and fibrin degradation products (FDP) (P less than 0.01), but not of PAI-2 (P greater than 0.1) as compared with less severely ill patients (meningitis and meningococcemia) (n = 25). A positive correlation existed between the admission (maximum) levels of LPS and PAI-1 (r = 0.86, P less than 0.0001). Decreasing admission levels of platelets were associated with increasing levels of PAI-1 (r = -0.55, P less than 0.001). After initiation of treatment with antibiotics and fresh frozen plasma, the PAI-1 levels declined rapidly. PAI-1 levels greater than 360 micrograms/L on admission predicted the development of a severe septic shock combined with renal impairment correctly in 12 of 13 patients (92%). None of 25 patients without multiple organ failure had PAI-1 levels greater than 260 micrograms/L. PAI-1 levels greater than 1850 micrograms/L were associated with 100% fatality. The results suggest that in the early phase of fulminant meningococcal septicemia an extensive plasmin generation occurs. On admission, however, high levels of PAI-1 seem to inhibit the plasmin generation, and thereby promote DIC.
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PMID:Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. 231 89

We utilized antisera specific for murine IL 1 alpha and IL 1 beta proteins to characterize cell-associated IL 1 according to two distinct criteria, immunochemical detection of radiolabeled IL 1 polypeptides and inhibition of IL 1 activity in cell lysates. Evidence is presented that IL 1 alpha and IL 1 beta are each synthesized by LPS-stimulated but not by unstimulated murine macrophages and accumulate within the cell as intracellular precursors in sizes of 33 kDa and 37 kDa, respectively. As judged by the respective rates of synthesis, IL 1 alpha was about 4-fold more abundant than IL 1 beta. Most (greater than or equal to 95%) of the cell-associated IL 1 activity was inhibited in the presence of the antiserum to IL 1 alpha, suggesting that the precursor of IL 1 beta is mostly biologically inactive. Incubation of cell lysates with papain but not with trypsin or plasmin markedly stimulates an increase in the level of cell-associated IL 1 beta activity and leads to the cleavage of 15-16 kDa carboxyl-terminal fragments from the IL 1 beta precursor. Together, these data indicate that proteolysis of the IL 1 beta precursor is required to generate bioactive IL 1 beta molecules and provide a basis for further investigations of the specific role of proteinases in processing the IL 1 beta precursor to a bioactive form.
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PMID:Proteolysis of the native murine IL 1 beta precursor is required to generate IL 1 beta bioactivity. 265 10

Mouse spleen cells were cultured for 4 days in RPMI 1640 medium with 5% fetal calf serum. The neutral proteinases trypsin and plasmin, and bacterial lipopolysaccharide LPS, all polyclonal B lymphocyte activators, stimulated the development of immunoglobulin producing cells as detected by the protein A plaque assay. At the same time, direct plaque forming cells reacting with mouse, human and rabbit IgG and the Fc fragment of human IgG were induced by the stimulants. The plaques could be inhibited by free IgG or Fc fragment. In the culture supernatants, IgM and IgM anti-IgG antibodies were detected by enzyme linked immunosorbent assays. Both general IgM and IgM anti-IgG antibodies increased under the influence of the proteinases and of LPS. The results are discussed in relation to rheumatoid factor production during inflammatory diseases.
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PMID:Neutral proteinases induce rheumatoid factor production in mouse spleen cell cultures. 622 74

Transforming growth factor-beta (TGF-beta) is secreted by most cells as a biologically inactive complex, called the large latent TGF-beta complex. The complex is comprised of latent TGF-beta binding protein (LTBP) and latent TGF-beta, which is mature TGF-beta associated noncovalently with its amino-terminal propeptides. LTBP is disulfide-linked to the amino-terminal propeptide of latent TGF-beta. Active TGF-beta is generated by release of TGF-beta from the complex. Generation of active TGF-beta by macrophages has been reported, but the activation mechanism has not been described. Latent TGF-beta activation by macrophages was characterized using serum-free cultures of resident and thioglycollate-elicited murine peritoneal macrophages that were either unstimulated or LPS-stimulated in vitro. Serum-free conditioned medium was assayed for TGF-beta using a quantitative luciferase-based bioassay. LPS-stimulated thioglycollate-elicited macrophages activated endogenous latent TGF-beta, whereas non-LPS-stimulated thioglycollate-elicited and resident macrophages generated undetectable levels of TGF-beta. Latent TGF-beta activation required plasmin and urokinase (uPA), uPA binding to the uPA receptor, interaction with the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor, tissue type II transglutaminase, and LTBP. A time-course analysis of latent TGF-beta activation revealed that maximal TGF-beta was generated after 24 h (25 +/- 5 pg/ml). TGF-beta formed within the initial 24 h modulated the plasminogen activator system by down-regulating uPA, suggesting that TGF-beta temporally modulated its own formation by regulating cell-associated uPA.
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PMID:Characterization of latent TGF-beta activation by murine peritoneal macrophages. 763 10

Recent advances in determining anti-thrombogenic functions of vascular endothelial cells are reviewed. The following anticoagulant and fibrinolytic systems of endothelial cells are physiologically important; (1) Endothelial cell-derived metabolites including prostacyclin and nitric oxide (NO) support platelet inactivity. (2) Antithrombin III and tissue factor pathway inhibitor (TFPI) bound to heparin-like proteoglycans on endothelial cell membrane inhibit activated serine protease coagulation factors such as thrombin, factor Xa and factor VIIa-tissue factor complex. (3) Thrombomodulin converts thrombin from procoagulant into anticoagulant. Thrombin associated to thrombomodulin on endothelial cells activates protein C. Activated protein C in concert with protein S bound to endothelial cell membrane inactivates factors Va and VIIIa. (4) A receptor for both tissue plasminogen activator and plasminogen on endothelial cells provides an efficient plasmin generating system. Perturbation of these anti-thrombogenic systems of endothelial cells is caused by endotoxin (LPS), cytokines such as interleukin-1 and tumor necrosis factor (TNF), and risk factors for atherogenesis including lipoprotein(a) and homocysteine may result in arterial or venous thrombosis with subsequent development of atherosclerosis.
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PMID:[Anticoagulant and fibrinolytic systems of the injured vascular endothelial cells]. 817 40

To identify some of the genes expressed in LPS-activated coelomocytes, we sequenced randomly chosen clones from a directionally constructed cDNA library to produce a set of expressed sequence tags (ESTs). Deduced amino acid sequences from 307 ESTs were compared with known protein sequences in GenBank, and significant matches to approximately 30% of the clones were identified. Eighty-nine clones matched to 55 different proteins, including several putative immune effector proteins. In this work, we show the first identification of an invertebrate homologue of a vertebrate C component. Another EST matches to several short consensus repeats that are characteristic of a variety of proteins, including CR/regulatory proteins and clotting factors. Additional putative immune effector genes include 1) a Kazal-type protease inhibitor that may function to inactivate bacterial proteases, 2) a C-type lectin similar to echinoidin, and 3) a serine protease with similarities to thrombin, elastase, haptoglobin, and plasmin. Other EST categories include 1) cell surface proteins and receptors, 2) proteins involved in signaling systems, 3) lysosomal and secreted proteins, 4) cytoskeletal and cytoskeletal modifying proteins, 5) general cell function proteins, 6) proteins with unknown function, and 7) ESTs without significant matches, 25 with open reading frames. Many of the ESTs identified in this study represent the types of genes expected to be used in lower deuterostome immune functions.
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PMID:Sea urchin genes expressed in activated coelomocytes are identified by expressed sequence tags. Complement homologues and other putative immune response genes suggest immune system homology within the deuterostomes. 854 10

TNF-stimulated gene 6 (tsg6), encoding a 35-kDa secretory glycoprotein (TSG-6), is induced in fibroblasts, chondrocytes, synovial cells, and mononuclear cells by the proinflammatory cytokines TNF-alpha and IL-1, or by LPS. Large amounts of TSG-6 protein were found in synovial fluids of patients with rheumatoid arthritis. TSG-6 protein forms a stable complex with components of the serine protease inhibitor, inter-alpha-inhibitor (I alpha I). In this work, we show that TSG-6 potentiates the inhibitory effect of l alpha l on the protease activity of plasmin. The plasmin/plasminogen activator system is important in the protease network associated with inflammation. To test the hypothesis that through their cooperative inhibitory effect on plasmin TSG-6 and l alpha l can modulate the protease network and thus inhibit inflammation, we examined the effect of TSG-6 on experimentally induced inflammation. Human recombinant TSG-6 protein showed a potent anti-inflammatory activity in the murine air pouch model of carrageenan- or IL-1-induced acute inflammation. The inhibitory effect of locally administered TSG-6 on the IL-1-induced cellular infiltration was comparable with that of systemic dexamethasone treatment. Two mutant TSG-6 proteins with single amino acid substitutions close to the N terminus showed a complete or partial loss of anti-inflammatory activity. The anti-inflammatory effect of the TNF/IL-1-inducible TSG-6 protein, along with its ability to inhibit protease action through interaction with l alpha l, suggests that TSG-6 production during inflammation is part of a negative feedback loop operating through the protease network.
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PMID:TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo. 856 67

The plasmin/plasminogen system of enzymes may be involved in leukocyte migration through the endothelial cell layer of the vascular wall during inflammatory processes associated with vascular injury, atherosclerosis, and sepsis. Synthesis of plasminogen activator inhibitor type 1 (PAI-1) by the endothelium may protect these cells and the subendothelial cell matrix from excessive degradation and retard leukocyte migration. We report in this work for the first time the down-regulation of both basal and thrombin- or endotoxin-induced PAI-1 in cultured human endothelial cells by the activated T cell product, IFN-gamma. Down-regulation of basal and thrombin- or endotoxin-induced endothelial PAI-1 protein by IFN-gamma was found to be both time and dose dependent. Decreases of up to 71% relative to thrombin- or endotoxin-treated controls, using an optimal IFN-gamma concentration of between 20 and 200 U/ml, were found for human macrovascular and microvascular endothelial cells. However, IFN-gamma did not appear to affect IL-1 alpha- and TNF-alpha-induced levels of PAI-1 protein or mRNA in these cells. Northern blot analysis paralleled protein results, showing decreases in specific endothelial cell thrombin- or LPS-induced PAI-1 mRNA expression, respectively, after incubation with IFN-gamma for 24 h. These results suggest a means by which the migration of circulating leukocytes through endothelial cell layers during inflammation may be facilitated.
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PMID:IFN-gamma inhibits thrombin- and endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells. 880 64


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