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)

Transforming growth beta (TGF-beta) has been proposed to have a role in bone remodeling by affecting the differentiation and activity of osteoblasts and osteoclasts and by inhibiting the production of proteinases, such as plasminogen activators (PAs). Studies on PAs have largely been based on data from nonhuman and fetal cell lines, however. The purpose of this study was to investigate the effect of TGF-beta on the PA activity of normal human osteoblast-like cells and to compare this with its action on the human osteosarcoma cell line MG-63. The action of interleukin-1 beta (IL-1 beta) was also assessed because it has been shown to increase PA activity in other connective tissue cell types. Normal osteoblast-like cells had low to undetectable basal urokinase (uPA) and tissue plasminogen activator (tPA) activity, which was significantly stimulated by TGF-beta 1. This action was shown to be dependent on transcription and new protein synthesis. TGF-beta 2 had a similar action. IL-1 beta did not stimulate PA activity. In contrast, the MG-63 cell line had high basal tPA and uPA activities. TGF-beta 1 decreased basal PA activity, the effect being most marked for uPA activity. IL-1 beta stimulated uPA and tPA activity. TGF-beta 1 inhibited IL-1 beta-stimulated uPA activity, but the effect on tPA was more variable. This study has shown that TGF-beta has opposite effects on the PA activity of the two osteoblast-like cell types studied. Care must therefore be used before extrapolating data from one cell type to another.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of transforming growth factor beta on the plasminogen activator activity of normal human osteoblast-like cells and a human osteosarcoma cell line MG-63. 148 22

Plasminogen activators (PAs) and/or plasmin may be involved in hematopoietic regulation. These enzymes release biologically relevant cytokines such as basic fibroblast growth factor (bFGF) from matrix and cell surfaces. In addition, transforming growth factor beta (TGF beta) and interleukin-1 beta (IL-1 beta) are converted from inactive to active forms by plasmin. Therefore, we studied the regulation of PAs and their specific inhibitors, PA inhibitor 1 (PAI-1) and PA inhibitor 2 (PAI-2), in human bone marrow stromal fibroblasts by IL-1 beta, bFGF, and TGF beta. All three cytokines stimulated PA secretion. IL-1 beta at 10(4) U/mL increased urokinase (u-PA) levels approximately 10-fold, bFGF at 0.2 ng/mL also increased production 10-fold, but increased predominantly tissue PA (t-PA) expression. TGF beta at 0.2 ng/mL increased u-PA production up to 300-fold. PAI-1 and PAI-2 are also regulated by these cytokines. IL-1 beta decreased PAI-1 levels by 50% and stimulated PAI-2 levels sixfold. bFGF had minimal effects on PAI-1 and TGF beta increased PAI-1 levels twofold. Neither of these agents had an effect on PAI-2 levels. Thus, three cytokines relevant to bone marrow physiology regulate PA and inhibitor production by human bone marrow stromal fibroblasts. In this manner PA and plasmin generation in specific microenvironments in the bone marrow may be one of the factors orchestrating the complex series of events, which results in an efficient exquisitely regulated hematopoietic process.
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PMID:Regulation of proteolytic activity in human bone marrow stromal cells by basic fibroblast growth factor, interleukin-1, and transforming growth factor beta. 153 45

The interleukin 1 (IL-1)-inducible mRNAs for plasminogen activator inhibitor type 2, manganese superoxide dismutase, and urokinase are overexpressed in old (greater than 70% of life-span completed) but not in young (less than 40% of life-span completed) human foreskin fibroblasts. Furthermore, the activity of this superoxide dismutase is greater in old than in young fibroblasts. IL-1 beta mRNA is detected by Northern blot analysis in old fibroblasts and its expression is further enhanced by a treatment with IL-1 alpha. IL-1 alpha and IL-1 beta mRNAs are detected in old foreskin and lung fibroblasts by a sensitive reverse transcription-PCR assay. IL-1 mRNA is consistently expressed after fibroblasts have completed 85% of their in vitro life-span; an assay with specific antibodies shows that IL-1 alpha is present in these fibroblasts. Prolonged treatment with IL-1 receptor antagonist decreases the levels of IL-1 alpha and of IL-1 alpha and IL-1 beta mRNAs. This observation suggests that IL-1 receptor antagonist inhibits an autocrine loop responsible for IL-1 expression. IL-1 mRNA accumulates in young fibroblasts treated with cycloheximide, suggesting that it is transcribed but unstable in these cells; accumulation of IL-1 mRNA in old fibroblasts may be due at least in part to increased stability. IL-1 alpha stimulates DNA synthesis in young fibroblasts but has progressively less effect as the cells age in culture. These data indicate that IL-1 is "constitutively" produced by aging fibroblasts and that IL-1 induces the expression of specific proteins in these cells. The mechanism for this constitutive production of IL-1 is explored in this paper.
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PMID:Expression of interleukin 1-inducible genes and production of interleukin 1 by aging human fibroblasts. 158 4

Diffuse alveolar damage, presenting clinically as adult respiratory distress syndrome, is characterized initially by widespread intra-alveolar fibrin deposition. Alveolar epithelial cells play a central role in the subsequent repair process. We have recently shown that alveolar epithelial cells have the capacity to promote fibrinolysis (Marshall, B. C., Sageser, D. S., Rao, N. V., Emi, M., and Hoidal, J. R. (1990) J. Biol. Chem. 265, 8198-8204) and may therefore directly participate in the extensive remodeling that follows acute lung injury. Because the tissue repair process occurs in an acute inflammatory setting, we investigated the effects of inflammatory mediators on urokinase-type plasminogen activator (u-PA) expression by pulmonary epithelial cells. We found that interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) upregulated PA activity in A549 human pulmonary epithelial cells. Biosynthetic labeling and immunoprecipitation showed that both cytokines caused marked accumulation of newly synthesized u-PA. Northern blot analyses demonstrated that both IL-1 beta and TNF-alpha induced relatively rapid accumulation of u-PA mRNA which did not require de novo protein synthesis and was substantially inhibited by glucocorticoids. Nuclear run-off transcription studies showed that both cytokines caused rapid transcriptional activation of the u-PA gene. While the effects of IL-1 beta and TNF-alpha were qualitatively similar, some differences emerged. Most notably, TNF-alpha led to a more sustained accumulation of u-PA mRNA than did IL-1 beta. In contrast to their effects on u-PA expression, IL-1 beta and TNF-alpha had minimal effect on PA inhibitor-1 expression. These effects of IL-1 beta and TNF-alpha, mediators known to play a key role in acute lung injury and inflammation, may promote lysis of alveolar fibrin by alveolar epithelium, thereby aiding in restoration of normal lung architecture.
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PMID:Pulmonary epithelial cell urokinase-type plasminogen activator. Induction by interleukin-1 beta and tumor necrosis factor-alpha. 159 74

We studied the effect of fibrinogen degradation products D, E, and D-dimer on a human promonocytic leukemia cell line, NOMO-1. After exposure to a 10(-5)-mol/L fragment D or D-dimer, the cells displayed macrophage-like characteristics, such as adherence to plastic surfaces, and showed approximately a twofold increase in response to the nitroblue tetrazolium reduction test. The secretion of interleukin-1 alpha (IL-1 alpha) into the medium was markedly stimulated by a 10(-5)-mol/L fragment D, E, and D-dimer, whereas a significant increase in IL-1 beta secretion was observed only in D-dimer-stimulated cells. In addition, D-dimer induced a rapid increase in urokinase-type plasminogen activator on day 1 (0.52 +/- 0.02 ng/mL v 0.07 +/- 0.01 ng/mL in the control culture) and a slow increase in plasminogen activator inhibitor-2 on day 5 (3.9 +/- 1.6 ng/mL v 1.2 +/- 0.2 ng/mL in the control culture). An increase in tissue factor (TF) was also demonstrated on the cell surface of NOMO-1 cells exposed to fragment D or D-dimer by indirect immunofluorescence using an anti-TF monoclonal antibody. Scatchard plot analysis showed that fragment D and D-dimer bound to the NOMO-1 cells with a kd of 3.3 nmol/L and 2.7 nmol/L, respectively. These results suggest that fragment D-dimer specifically stimulates cells of monocyte-macrophage lineage to secrete key substances that regulate blood coagulation, fibrinolysis, and inflammation.
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PMID:FDP D-dimer induces the secretion of interleukin-1, urokinase-type plasminogen activator, and plasminogen activator inhibitor-2 in a human promonocytic leukemia cell line. 184 45

Interleukin 1, derived from human placenta, stimulates plasminogen activator activity in human articular chondrocytes. The stimulation of plasminogen activator activity can be abolished by preincubation of placental interleukin 1 with an antiserum to homogeneous 22K factor, a species of interleukin 1 beta, indicating that the stimulation of plasminogen activator activity is due to interleukin 1 and not contaminating factors. Chondrocytes produce three species of plasminogen activator, with apparent Mr approximately 50,000, 65,000 and 100,000 as determined after sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis with gels containing casein and plasminogen. Both placental interleukin 1 and 22K factor enhance the production of the species of Mr approximately 65,000 and 100,000. Comparison of the mobility of the plasminogen activator species on SDS-polyacrylamide gel electrophoresis with human urokinase (u-PA) and human melanoma tissue-type plasminogen activator (t-PA) and studies with antibodies to these enzymes indicate that the Mr approximately 50,000 species is a u-PA and the Mr approximately 65,000 a t-PA. The Mr approximately 100,000 species is possibly an enzyme-inhibitor complex. Interleukin 1 therefore appears to enhance the production of t-PA and a putative enzyme-inhibitor complex. Abolition of plasminogen activator activity in the fibrin plate assay with antibodies to t-PA and u-PA also confirms enhanced t-PA production on interleukin 1 stimulation, though there is also evidence for increased cell-associated production of u-PA.
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PMID:Interleukin 1 preferentially stimulates the production of tissue-type plasminogen activator by human articular chondrocytes. 310 96

Cytokines capable of stimulating cartilage resorption have frequently been identified as 'interleukin-1 (IL-1)-like' peptides. In this study for the first time we have employed homogeneous recombinant IL-1 alpha and IL-1 beta in an all-human culture system to define the effects of IL-1 on articular cartilage and chondrocytes in culture. Recombinant IL-1 (10-100 U/ml) could stimulate cartilage resorption, although the maximum degree of tissue breakdown rarely reached the levels obtained when cartilage was treated with crude mononuclear-cell conditioned medium or all-trans retinoic acid (1 microM) over a similar time course. Levels of plasminogen activator (PA) activity, a neutral proteinase which may contribute to cartilage destruction in arthritis, increased markedly in the cartilage/chondrocyte culture supernatants and in the chondrocyte cell layers in response to the stimulation of cultures with recombinant IL-1 (1-100 U/ml). Elevated levels of PA activity were detectable after 4-8 h stimulation of the chondrocytes with IL-1 while characterization of the PA activities indicated that both types of PA activity were expressed, viz. urokinase-type PA (u-PA) and tissue-type PA (t-PA). Both IL-1 alpha and IL-1 beta could elicit these responses and their effects were comparable for a given dose. These studies show definitively that pure IL-1, free from contaminating cytokines, is capable of inducing human cartilage resorption and stimulating the expression of two types of PA activity by chondrocytes. In contrast to IL-1, retinoic acid increased the detectable levels of only u-PA in the chondrocyte cell layers. Chondrocyte u-PA may have an important role in cartilage degradative processes since it is one of the few neutral proteinases now known to be increased in activity in retinoid-stimulated cartilage.
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PMID:Recombinant human interleukin-1 stimulates human articular cartilage to undergo resorption and human chondrocytes to produce both tissue- and urokinase-type plasminogen activator. 314 27

In continuation of earlier observations on the involvement of interleukin-1 (IL-1) in ovarian function, we examined the ability of IL-1 to modulate plasminogen activator (PA) activity and prostaglandin (PG) synthesis in human granulosa lutein cells (GLCs). Toward this goal, GLCs were obtained from women undergoing in vitro fertilization, preincubated with 10% fetal calf serum for 48 h, and subsequently cultured for 48 h in serum-free media in the absence or presence of IL-1 beta (10 ng/mL). Cellular PA activity was measured by plasminogen-dependent cleavage of the chromogenic substrate H-D-valyl-L-leucyl-L-lysine-p-nitroanilide (S-2251). Prostaglandin E (PGE) levels were assayed by conventional RIA. Exposure of GLCs to IL-1 resulted in a 50% increase in PGE production, a 33% suppression of PA activity, and a 75% increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. The inhibitory capacity was attributable to an IL-1-mediated increase in PA inhibitor type-1 (PAI-1) production, inasmuch as urokinase inhibition could be abolished by the administration of a polyclonal antihuman PAI-1 immunoglobulin G. IL-1 treatment had no effect on plasmin or trypsin inhibition. Exposure of GLCs to IL-1 receptor antagonist abolished the ability of IL-1 to enhance PA inhibitory activity and PGE production, thereby establishing specific IL-1 receptor-mediated effects. The ability of IL-1 to suppress PA activity and to produce PAI-1 persisted in the presence of indomethacin, a potent inhibitor of PG synthesis. Likewise, transforming growth factor-beta 1 suppressed the ability of IL-1 to stimulate PGE production without affecting the IL-1-induced effects on the PA system. The present findings suggest a pluripotent response of GLCs to IL-1, characterized by the induction of PAI-1 and the suppression of PA occurring concurrent with, but independent of, PG production. These observations support the potential involvement of IL-1 in the regulation of human ovulatory processes.
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PMID:Interleukin-1-mediated stimulation of prostaglandin E production is without effect on plasminogen activator activity in human granulosa lutein cell cultures. 755 90

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a suspected human carcinogen, is believed to produce its toxic and carcinogenic effects by altering expression of growth-regulatory factors. TCDD alters the expression of a number of specific genes in the transformed human keratinocyte cell line, SCC-12F, including transforming growth factor-alpha (TGF-alpha), TGF-beta 2, plasminogen activator inhibitor-2 (PAI-2), and interleukin-1 beta (IL-1 beta). To determine whether nontransformed human keratinocytes (NHK) respond similarly to TCDD, we studied the effect of TCDD on NHK growth and differentiation, and gene expression. NHK were treated prior to reaching confluence with 10 nM TCDD and evaluated at 1, 2, 3, and 5 days following treatment for the effect of TCDD on cell number, morphology, involucrin levels, mRNA expression, and protein concentrations. TCDD altered both the mRNA and protein concentrations of TGF-alpha, TGF-beta 2, PAI-2, and IL-1 beta. The mRNA level for u-PA, a plasminogen activator that is inhibited by PAI-2, was not altered following TCDD treatment. However, u-PA protein levels were significantly induced, indicating an effect of TCDD on u-PA synthesis, secretion, or turnover. TCDD enhanced NHK differentiation, as determined by an increase in involucrin expression. TCDD did not alter cell number or colony-forming efficiency, suggesting that TCDD was enhancing the differentiation of cells already committed to terminal differentiation. These results demonstrate that treatment of NHK with TCDD results in the simultaneous modulation of expression of a number of growth-regulatory proteins and suggest that the growth and differentiation response of human keratinocytes to TCDD is due to a complex interaction of these diverse proteins.
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PMID:Regulation of gene expression and acceleration of differentiation in human keratinocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 804 63

It is often assumed that macrophage-colony stimulating factor (M-CSF) or CSF-1, as well as granulocyte macrophage-CSF (GM-CSF), can induce inflammatory mediator production by monocytes/macrophages. We demonstrate with elutriation-purified human monocytes that, in contrast to lipopolysaccharide, recombinant human CSF-1 does not induce secretion of prostaglandin E2, interleukin-6 (IL-6), IL-1 beta, or tumor necrosis factor alpha, as measured by immunoassay; however, increased urokinase-type plasminogen activator (u-PA) activity in cell lysates and mRNA was observed. Similar results were obtained when the monocytes were treated with recombinant human GM-CSF. Such increased u-PA expression may contribute to the function of CSF-1 at sites of inflammation.
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PMID:Effects of macrophage-colony stimulating factor on human monocytes: induction of expression of urokinase-type plasminogen activator, but not of secreted prostaglandin E2, interleukin-6, interleukin-1, or tumor necrosis factor-alpha. 831 54


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