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:3.4.21.73 (urokinase-type plasminogen activator)
10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plasminogen activator (PA)/plasmin system has been implicated in the inflammation and connective tissue remodelling occurring in arthritic joints. PA activity is detected in cultures of human monocytes, synoviocytes and chondrocytes and can be regulated by a variety of cytokines found in diseased joints; PA inhibitors (PAI-1 and/or PAI-2) are also produced by these cells. We have shown that human monocytes can synthesize both urokinase-type PA (u-PA) and tissue-type PA (t-PA). One cytokine present in rheumatoid synovial fluids, granulocyte macrophage colony stimulating factor (GM-CSF), stimulates monocyte u-PA production; since this cytokine can also be produced by activated monocytes and other cell types in joints, than a "CSF network" can be produced leading to u-PA production. Another monocyte cytokine, interleukin 1, causes human synoviocytes to increase their u-PA expression, a response which can be dependent on the presence of endogenous cyclooxygenase products; this cytokine also causes human chondrocytes and cartilage tissue to produce increased u-PA and t-PA activity, i.e., under conditions during which cartilage is resorbed.
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PMID:Regulation of plasminogen activator activity in arthritic joints. 190 74

Protein kinase C (PKC) activation is regulated by Ca2+, phospholipids, diacylglycerol (DAG) and fatty acids. Phorbol myristate acetate (PMA) which mimics the effect of DAG on PKC induces transcriptional activation of the urokinase-type plasminogen activator (u-PA) gene in LLC-PK1 cells. We examined in the present work the relationships between PKC activity, fatty acids, and u-PA synthesis in this cell line. We showed that H7, an inhibitor of PKC, inhibited the PMA-induced u-PA synthesis by LLC-PK1 cells. PMA-induced u-PA synthesis was enhanced by eicosatetraynoic acid (ETYA), a competitive inhibitor of both the lipoxygenase and cyclooxygenase pathways and inhibited by nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway. Three other unrelated lipoxygenase inhibitors (phenidone 100 microM, BW755 50 microM and diethylcarbamazine 50 microM) had no effect on u-PA biosynthesis. Two polyunsaturated fatty acids other than ETYA, arachidonic acid and linoleic acid, also potentiated the PMA effect and a lipoxygenase derivative, 12 hydroxyeicosatetraenoic acid (12 HETE), did not modify the basal and PMA-stimulated u-PA syntheses. PKC activity purified from cytosol of LLC-PK1 cells was stimulated by addition of 16 nM PMA in vitro and this effect was blunted by simultaneous addition of 5 microM NDGA. By Northern blot analysis using a pig u-PA cDNA probe we found that PMA increased the steady state level of u-PA mRNA after 2 h of incubation and that NDGA inhibited this effect. These data suggest that NDGA inhibits PMA-stimulated PKC activity in intact cells leading to a decrease of u-PA mRNA level and u-PA biosynthesis in PMA-stimulated LLC-PK1 cells. Polyunsaturated fatty acids have opposite effects.
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PMID:Nordihydroguaiaretic acid inhibits urokinase synthesis by phorbol myristate acetate-stimulated LLC-PK1 cells. 212 15

Human diploid fibroblasts were cultured on microcarriers made from DEAE-dextran, denatured collagen, DEAE-dextran linked to denatured collagen, and glass. Cells grown on these four substrates were examined for the production of proteolytic enzymes and arachidonic acid metabolites. Culture fluids from cells grown on the DEAE-dextran microcarriers contained the highest amounts of proteolytic enzyme activity. Both plasminogen-independent and plasminogen-dependent fibrinolytic activities were present and the plasminogen-dependent activity seemed to result from the presence of both urokinase and tissue plasminogen activator. Culture fluid from the cells grown on the glass microcarriers contained the least amount of protease activity, and nearly all of the plasminogen-activator activity seemed to be of the urokinase type. Protease activity in the culture fluids of cells grown on the other two substrates were intermediate. With regard to arachidonic acid metabolites, cells grown on the DEAE-dextran microcarriers produced the highest amounts of cyclooxygenase products but very low levels of lipoxygenase metabolites. Cells grown on the other three substrates produced comparable amounts of various cyclooxygenase products (lower than that produced by cells on the DEAE-dextran substrate). Cells grown on the glass microcarriers also produced detectable amounts of two lipoxygenase metabolites--leukotriene B4 and leukotriene C4. Inasmuch as both proteolytic enzymes and arachidonic acid metabolites regulate basic cell properties, the differential amounts of these metabolites observed in the culture fluids on the various substrates may contribute to the biological differences that exist on these substrates.
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PMID:Proteolytic enzymes and arachidonic acid metabolites produced by MRC-5 cells on various microcarrier substrates. 309 7

The release of plasminogen activators (PA) from human isolated glomeruli has been studied by a sensitive radioenzymatic assay using 125I-fibrin coated tubes and plasminogen. The glomerular fibrinolytic activity (GFA) was detectable after 15 minutes of incubation. Then it increased with time, the glomerular protein concentration, and with the plasminogen concentration (P less than 0.001 for all). CaCl2 (1 mM) increased the GFA (9.7 +/- 0.9 versus 4.9 +/- 0.4 micrograms fibrin/mg/30 min, P less than 0.05). The GFA was also enhanced when pH increased. Arachidonic acid (AA, 1 to 20 micrograms/ml) increased the GFA in a saturable manner. Inhibitors of cyclooxygenase (aspirin) or of lipoxygenase (nordihydroguaiaretic acid) did not modify the basal and AA-stimulated GFA. Other polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), eicosatrienoic acid (ETA), eicosatetraynoic acid (ETYA), or dihomo-gamma-linoleic acid (DHL), also stimulated the GFA whereas linoleic acid and oleic acid did not. Polyunsaturated fatty acids also stimulated the fibrinolytic activity of glomerular supernatants. Specific antibodies to t-PA, and to a lesser extent to u-PA, decreased this fibrinolytic activity whether or not AA was added. Furthermore, AA and EPA were found to increase the activity of purified u-PA and t-PA. We conclude that human glomeruli release both t-PA and u-PA, and that this release is increased by calcium and alkaline pH. The polyunsaturated fatty acids enhanced the GFA, mainly by a stimulatory effect of PA activity rather than an increased release of PA from glomerular cells.
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PMID:Polyunsaturated fatty acids increase fibrinolytic activity of human isolated glomeruli. 309 75

P388D1 is a murine macrophage cell line which spontaneously secretes plasminogen activator (PA; activated function) and lysozyme (LYS; constitutive function). Compounds which decrease PA secretion without affecting LYS secretion have potential as "down-regulators" of macrophage function and, hence, of the immune system. Glucocorticoids (e.g., dexamethasone, IC50 less than 0.01 microM) and auranofin (IC50 = 1 microM) are positive in this model. In contrast, cyclooxygenase inhibitors (indomethacin, ibuprofen and piroxicam, all at 1 microM) boost PA secretion; lipoxygenase inhibitors (REV-5901, NDGA and piriprost, all at 10 microM) have little or no effect. Dexamethasone, but not auranofin, induces a urokinase-inhibitory activity which elutes between 0.13 and 0.19 M NaCl upon anion exchange HPLC (TSK-DEAE-5-PW). Fibrin overlay following SDS-PAGE of the HPLC peak reveals a urokinase-inhibitory band at approximately 90 Kd.
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PMID:Pharmacological modulation of plasminogen activator secretion by P388D1 cell line. 312 May 14

Intrinsic plasminogen activators (PA) were tested in euglobulins (eug) of platelet poor plasma (PPP) with and without washed platelets (WP), treated or not with urokinase (UK), streptokinase (SK), collagen (Col) and aspirin (ASA) using fibrin plates method. A significant decrease of the fibrinolytic activity related to the presence and number of platelets was observed. We confirm the presence of platelet anti-UK and anti-SK activities. The former appears to be higher than the other activity. Low and high concentrations of Col stimulated the release of plasminogen activator-inhibitors (PA-I) from platelets, and ASA could not modify this release. Besides ASA might inhibit some PA release. The high concentration of Col was capable to release anti-UK and anti-SK activities from platelets and perhaps other intrinsic PA-I. The low concentration of Col was only capable to release intrinsic PA-I, suggesting that anti-UK and anti-SK needed a stronger stimuli to be released than intrinsic PA-I. We must consider the possibility that the PA-I and/or activators could be released by different metabolic pathways other than cyclooxygenase pathway.
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PMID:Aspirin effect on the release of plasminogen activator inhibitors by human platelets. 314 64

The aim of the present study was to determine the role of transforming factor alpha (TGF alpha) and beta (TGF beta) in the regulation of prostaglandin (PG) secretion, and the relationships between PG and plasminogen activator (PA) activity in hen granulosa cells during ovarian follicular development. Cells from the first (F1), third (F3), and fifth and sixth (F5-6) largest preovulatory follicles were cultured for up to 21 h in the presence of TGF alpha (0.1-10 ng/ml) and/or TGF beta (4-20 ng/ml) or TGF alpha together with a cyclooxygenase inhibitor, indomethacin (0.05-0.5 microM). The release of PG into the incubation medium was determined by RIA. Cell-associated (PAc) and secreted (PAs) PA activities were measured by a fibrinolysis assay and characterized by zymography. Basal PGF secretion from F1, F3, and F5-6 cells was 2.2 +/- 0.3, 2.2 +/- 0.5, and 1.1 +/- 0.3 ng/micrograms DNA, respectively, and was higher than that of PGE. Basal total PA (PAc+PAs) activity from F1, F3, and F5-6 cells was 41 +/- 13,261 +/- 68, and 958 +/- 268 x 10(3) cpm/micrograms DNA, respectively. TGF alpha stimulated PG secretion and PA activity in a dose-dependent manner. The TGF alpha-induced PA activity was predominantly associated with a molecular mass of 30-35 kDa, corresponding to that of urokinase PA. The stimulation of PG secretion by TGF alpha was maximal in F3 and F1 granulosa cells whereas PA activity in the presence of TGF alpha was highest in cells from F5-6 follicles.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Avian granulosa cell prostaglandin secretion is regulated by transforming growth factor alpha and beta and does not control plasminogen activator activity during follicular development. 781 60

The purpose of this study was to characterize the stimulus that activates the 5-lipoxygenase pathway in human peripheral monocytes (PM) during the process of contact activation. Incubation of PM, but not of polymorphonuclear leukocytes (PMN), in contact-activated, recalcified plasma induced a time-dependent release of leukotrienes (LT). The presence of platelets was required for the generation of cysteinyl-LT, but LTB4 formation also proceeded in their absence, although to a lesser extent. Plasmin, presumably generated via the intrinsic fibrinolytic pathway, was liable for the 5-lipoxygenase stimulation during contact activation inasmuch as (1) the 5-lipoxygenase pathway in PM was stimulated by contact-activated, recalcified, autologous or homologous plasma, but not by factor XII-deficient or prekallikrein-deficient plasma; (2) lysine analogs such as N alpha-acetyl-L-lysine, 6-aminohexanoic acid (6-AHA), or trans-4- (aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), which inhibit plasmin(ogen) binding to PM plasmin(ogen) binding sites, concentration-dependently reduced the cysteinyl-LT release; (3) plasminogen activators such as urokinase or streptokinase concentration-dependently enhanced the cysteinyl-LT release up to 10 and 1,000 IU/mL, respectively, while higher concentrations were less effective leading to bell-shaped concentration-response curves; (4) plasmin inhibitors such as aprotinin or alpha 2-antiplasmin concentration-dependently inhibited the cysteinyl-LT release; and (5) preincubation of plasma with monoclonal antibodies directed against plasminogen and capable of preventing plasminogen activation blocked the contact-mediated 5-lipoxygenase stimulation. Moreover, incubation of PM with plasmin, but not with plasma kallikrein, in Hanks' balanced salt solution (HBSS)-bovine serum albumin (BSA) 0.4% triggered a concentration-dependent release of LTB4 up to 0.1 caseinolytic units (CU)/mL, with higher concentrations being less effective. By contrast, release of cyclooxygenase metabolites such as thromboxane (TX) B2 and prostaglandin (PG) E2 was not stimulated by plasmin, indicating specificity for the 5-lipoxygenase pathway. With plasmin as a hitherto unknown stimulus of the 5-lipoxygenase pathway in PM, a novel link between contact activation and inflammation has been established.
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PMID:Contact activation triggers stimulation of the monocyte 5-lipoxygenase pathway via plasmin. 814 60

In previous studies conducted in rats and in women, we have shown that oral contraceptive (OC) administration induced a platelet hyperaggregation simultaneously with an increased platelet lipid biosynthesis which might be related to lipid peroxidation. In the present study, we specifically studied the arachidonic acid and the fibrinolytic pathways in relation to the fatty acid composition in female rats treated for 6 weeks with OC (ethinyl estradiol plus lynestrenol). We found that platelets of treated animals were not only hyper-responsive to thrombin and ADP, but also to sodium arachidonate. In addition, the results of the thrombin-induced release of labeled arachidonic acid pre-incorporated into platelet membrane phospholipids showed an increased biosynthesis of lipoxygenase and cyclooxygenase metabolites after OC treatment. These data indicated a stimulated platelet arachidonate metabolism in OC animals compared to controls which was further confirmed by the increased thrombin-induced production of thromboxane B2 (TXB2) as measured with a radioimmunoassay. The platelet thrombin-stimulated TXB2 biosynthesis was inhibited in vitro in the presence of 500 mu M aspirin and 1 mM vitamin E; the erythrocytes from OC animals compared with controls presented an enhanced in vitro susceptibility to free radical-induced hemolysis. These data indicated that a free radical mediated-process might occur. This hypothesis is confirmed by an increase of plasma lipid peroxidation parameters (conjugated dienes, lipid peroxides, thiobarbituric acid reactive substances). After OC-treatment, a decrease in plasma and platelet long chain polyunsaturated fatty acids, particularly (n-3), is in keeping with this idea. Furthermore, the results of the peritoneal macrophage-dependent fibrinolytic activity indicated that OC induced a drastic decrease in urokinase plasminogen activator activity which might further contribute to the platelet hyperactivity. Altogether these data suggest that besides the reported increase in clotting factors, platelet hyperactivity, possibly through a stimulated free radical-induced arachidonic acid metabolism, might be involved in the known high thrombogenic risk observed in OC users.
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PMID:Enhanced platelet thromboxane synthesis and reduced macrophage-dependent fibrinolytic activity related to oxidative stress in oral contraceptive-treated female rats. 912 95

We investigate the regulation of plasminogen activator inhibitor-2 (PAI-2) in murine macrophages. PAI-2 mRNA was inducible by bacterial lipopolysaccharide (LPS) in primary cells and macrophage-like cell lines. Evidence is presented for a role for autocrine factors, including cyclooxygenase products but not the cytokines tumor necrosis factor alpha or interferon-beta (IFN-beta). PAI-2 mRNA levels generally varied inversely from those of its target, urokinase-type plasminogen activator (uPA), and the macrophage growth factor CSF-1, which induces uPA, inhibited PAI-2 expression in cells treated subsequently with LPS. Expression of PAI-2 was distinct from that of other LPS-inducible genes in terms of induction time course, LPS dose response, and sensitivity to co-stimulation with IFN-gamma. Induction of PAI-2 mRNA in subclones of the cell line RAW 264 was not uniform, reflecting heterogeneous expression in the parent line. The expression pattern of PAI-2 is discussed in terms of a possible role in LPS-induced pathology such as septicemia.
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PMID:Regulation of the plasminogen activator inhibitor-2 (PAI-2) gene in murine macrophages. Demonstration of a novel pattern of responsiveness to bacterial endotoxin. 1041 Oct 6


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