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)

When a confluent monolayer of bovine aortic endothelial (BAE) cells is wounded with a razor blade, endothelial cells (ECs) spontaneously move into the denuded area. If bovine pericytes or smooth muscle cells (SMCs) are plated into the denuded area at low density, they block the movement of the ECs. This effect is dependent upon the number of cells plated into the wound area and contact between ECs and the plated cells. Antibodies to transforming growth factor-beta 1 (TGF-beta 1) abrogate the inhibition of BAE cell movement by pericytes or SMCs. TGF-beta 1, if added to wounded BAE cell monolayers, also inhibits cell movement. When cultured separately, BAE cells, pericytes, and SMCs each produce an inactive TGF-beta 1-like molecule which is activated in BAE cell-pericyte or BAE cell-SMC co-cultures. The activation appears to be mediated by plasmin as the inhibitory effect on cell movement in co-cultures of BAE cells and pericytes is blocked by the inclusion of inhibitors of plasmin in the culture medium.
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PMID:Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. 252 31

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

Receptors for urokinase (uPA) and plasminogen provide a mechanism to direct the cellular activation of plasminogen. The regulation of these receptors is important for several macrophage functions. In these studies, the effect of transforming growth factor-beta 1 (TGF-beta 1) on uPA, uPA receptor, and plasminogen receptor expression by human THP-1 macrophage was examined. TGF-beta 1 induction of uPA expression by THP-1 cells was differentiation dependent. Suspension and adherent cultures expressed similar constitutive levels of uPA. Exposure of adherent cells to TGF-beta 1 led to a dose- and time-dependent increase in uPA activity which was paralleled by an increase in uPA antigen and uPA mRNA. In contrast, uPA expression by suspension cultures was unresponsive to TGF-beta 1. The differential response exhibited by suspension and adherent THP-1 cells may reflect differences in their expression of TGF-beta 1 receptors, since when assayed by crosslinking techniques, suspension cells primarily expressed a 65 kDa receptor; whereas, the adherent cells expressed 65 and 100 kDa receptors. TGF-beta 1-induced alterations in uPA receptor expression by adherent THP-1 cells were examined by quantitating membrane-bound uPA activity. Membrane-bound uPA activity increased three-fold when cells were incubated with TGF-beta 1. The increase in membrane-uPA activity expressed by TGF-beta 1-treated cells was not due to increased uPA receptor occupancy since incubation of either control or TGF-beta 1 primed cells with exogenous uPA did not lead to an increase in membrane-bound uPA activity. Furthermore, immunoreactive uPA receptor was increased in TGF-beta 1-treated cells. Following incubation with plasminogen, membrane-bound plasmin activity increased three-fold in TGF-beta 1-treated cells. However, no change in immunoreactive membrane-bound plasmin(ogen) was observed. In addition, binding of 125I-Lys-plasminogen to THP-1 cells was not affected by TGF-beta 1 treatment. We conclude that TGF-beta 1 stimulates membrane-bound plasmin activity, without affecting plasminogen receptor expression, through the up-regulation of uPA and the uPA receptor expression.
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PMID:THP-1 macrophage membrane-bound plasmin activity is up-regulated by transforming growth factor-beta 1 via increased expression of urokinase and the urokinase receptor. 762 80

Monolayer cultures of human epithelial and endothelial cells were used to study the association of latent transforming growth factor-beta 1 (TGF-beta 1) to extracellular matrices and its release and activation during matrix degradation. Human umbilical vein endothelial cells and embryonic lung fibroblasts produced relatively high levels of TGF-beta 1, its propeptide (beta 1-latency-associated protein), and latent TGF-beta-binding protein and incorporated latent TGF-beta 1 into their matrices as shown by immunoblotting. Amnion epithelial cells produced lower levels of these proteins. Confluent cultures of epithelial cells were exposed to matrix-degrading proteases and glycosidases. Mast cell chymase, leukocyte elastase, and plasmin efficiently released matrix-bound latent TGF-beta 1 complexes, while chondroitinase ABC and heparitinases were ineffective. The ability of the proteases to activate recombinant latent TGF-beta 1 was tested using growth inhibition assays and a novel sodium deoxycholate-polyacrylamide gel electrophoresis followed by immunoblotting. Sodium deoxycholate solubilized M(r) 25,000 TGF-beta 1 but did not dissociate high M(r) latent TGF-beta 1 complexes, allowing separation of these forms by polyacrylamide gel electrophoresis. Mast cell chymase and leukocyte elastase did not activate latent TGF-beta 1, suggesting that its release from matrix and activation are controlled by different mechanisms. The release of TGF-beta from the matrix by leukocyte and mast cell enzymes may contribute to the accumulation of connective tissue in inflammation.
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PMID:Human mast cell chymase and leukocyte elastase release latent transforming growth factor-beta 1 from the extracellular matrix of cultured human epithelial and endothelial cells. 787 40

The release of latent transforming growth factor-beta 1 (TGF-beta 1), and conversion to the biologically active peptide, has been investigated in porcine thyroid follicular cells maintained in primary monolayer culture. Analysis by radioreceptor assay of medium conditioned for 72 h by subconfluent thyroid monolayers showed that a high proportion of the expressed TGF-beta 1 peptide was in the active form. Medium conditioned by iodide (10 mumol/l)-treated follicular cells contained higher levels of both active and total TGF-beta 1 than were present in medium conditioned by untreated cells. Exposure of cells to iodide also led to a marked decrease in [methyl-3H]thymidine incorporation that was relieved by immunoadsorption with a neutralizing antiserum against the active form of TGF-beta 1. Inclusion of a low dose (80 units/l) of porcine plasmin led to a small increase in incorporation of [methyl-3H]thymidine, while higher doses of plasmin (1250-5000 units/l) or plasminogen (100 mg/l) significantly reduced [methyl-3H]thymidine incorporation. This inhibition was effectively reversed by immunoadsorption of TGF-beta 1 from the medium during the test incubations. The study therefore provides direct evidence for a stimulatory role of thyroidal iodide in enhancing the release of latent TGF-beta 1 peptide, and suggests that in normal thyroid follicular cells, as in other TGF-beta 1 producing epithelia, post-secretory processing to the biologically active molecule occurs through an endogenous cellular mechanism. It appears likely that plasmin, generated locally within the thyroid follicular microenvironment, may play a fundamental role in effecting this conversion.
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PMID:Porcine thyroid follicular cells in monolayer culture activate the iodide-responsive precursor form of transforming growth factor-beta 1. 789 Oct 27

Although chronic progressive tubulointerstitial (TI) disease plays a critical role in the outcome of patients with primary glomerular lesions, the basic mechanisms that generate the TI damage remain unclear. This review focuses on recent insights into this process that originate primarily from studies of animal models of glomerular injury. The acute phase, which is often clinically silent, is characterized by tubular epithelial cell injury and interstitial inflammation. Proposed mediators of tubular injury include antibodies, lysosomal enzymes, obstruction, reactive oxygen metabolites, and complement. Damaged tubules may regenerate or undergo necrosis or apoptosis. The identification of the molecular mediators of mononuclear cell recruitment to the interstitium is of current interest because of evidence that monocytes/macrophages play a key role in progressive interstitial scarring through the release of fibrosis-promoting cytokines, particularly transforming growth factor-beta 1 (TGF-beta 1). Events linked to the initiation of interstitial inflammation include the deposition of antibodies or immune complexes along the tubular basement membranes, T cell-dependent mechanisms, glomerular factors, and factors linked to proteinuria. Several molecules likely regulate the interstitial migration of circulating monocytes, although the critical mediators are presently unknown. Candidates include chemotactic factors such as intercrines, growth factors, complement, lipid factors, osteopontin, and monocyte adhesion molecules (beta 1 integrins, beta 2 integrins, and L-selectins). The hallmark of the chronic phase of TI damage is interstitial fibrosis. Of the several candidate fibrogenic cytokines, to date, only TGF-beta 1 has been studied in any detail. TGF-beta 1 is produced by interstitial inflammatory cells and appears to trigger increased matrix production by perivascular and interstitial fibroblasts. Awaiting clarification is the role of tubular cells in vivo as a source of fibrogenic cytokines or as a site of increased matrix synthesis, activities they do perform in vitro. Preliminary studies suggest that interstitial fibrosis may also be due in part to the failure of matrix degradation by metalloproteinases and plasmin as a result of the overexpression of the enzyme inhibitors. The existence of an intrarenal matrix-degrading enzyme cascade suggests that renal fibrosis may be reversible, at least to a limited extent. In summary, during the early stage of glomerular injury, numerous cellular and molecular mediators of acute interstitial disease are activated and ultimately converge on common pathways that lead to progressive renal scarring.
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PMID:Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions. 789 92

Smooth muscle cells (SMCs) cultured alone exhibit characteristic "hill and valley" macroscopic growth features. We studied smooth muscle cells cocultured with endothelial cells and the effect of transforming growth factor beta 1 on smooth muscle cells: Bovine smooth muscle cells were plated on 13 microns-thick semipermeable membranes. Smooth muscle cells were cultured either alone (in Dulbecco's Modified Eagles Media/2.5% calf serum, four wells/group); with neutralizing anti-transforming growth factor-beta 1 antibody (10 micrograms/ml); with the protease inhibitor aprotinin (prevents plasmin-mediated activation of transforming growth factor-beta 1, 200 mg/ml); or in the presence of confluent bovine endothelial cells cocultured on the opposite side of the membrane before plating smooth muscle cells. After 72 hours in culture smooth muscle cell organizational growth characteristics were examined by light microscopy. Hill and valley formation by smooth muscle cells resulted in areas of the membrane becoming devoid of smooth muscle cells, whereas other areas developed multilayered densely populated smooth muscle cells. Computed planimetry was used to measure this bare surface area to quantitate the extent of hill and valley growth, which was compared between groups by analysis of variance. Smooth muscle cells cultured alone demonstrated prominent hill and valley formation with a bare surface area of 2.64 +/- 0.51 mm2. Smooth muscle cells exposed to transforming growth factor-beta 1 antibody had much less hill and valley formation (bare surface area 0.92 +/- 0.29, p < 0.01), whereas aprotinin virtually prevented hill and valley formation (bare surface area 0.0, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of endothelial cells and transforming growth factor-beta 1 on cultured vascular smooth muscle cell growth patterns. 796 14

The present study has investigated the relative levels and interconversion of latent and active forms of transforming growth factor-beta 1 (TGF-beta 1) in human thyroid follicular cell cultures derived from sporadic non-toxic goitres. Northern blotting of RNA extracted from 72-h cultures revealed a 2.5 kb mRNA transcript hybridizing with a cDNA probe for latent TGF-beta 1, the intensity of which was doubled in cells exposed to NaI (10 mumol/l). Radioreceptor assay of follicular cell-conditioned medium for TGF-beta 1 content confirmed a similar enhancing effect of iodide. The endogenous active component of TGF-beta 1 present in conditioned medium represented only a minor fraction of the total TGF-beta 1 content, this fraction was not enhanced by exposure of follicular cells to iodide. The low level of endogenous active TGF-beta 1 in medium conditioned by either control or iodide-treated cells was confirmed by immunoadsorption with a precipitating antiserum against active TGF-beta 1, when such cells failed to show a reversal of the iodide-induced decrease in [methyl-3H]thymidine incorporation into trichloroacetic acid-precipitable material. In contrast to the inhibitory effect of iodide on de novo DNA synthesis, which appeared not to reflect an increase in active TGF-beta 1, the inhibitory effects of plasminogen (100 mg/l) or plasmin (2000 U/l) on [methyl-3H]thymidine incorporation into thyroid cells were reversible by TGF-beta 1 immunoadsorption. This provides evidence that the plasmin-mediated inhibition of DNA synthesis in thyroid follicular cells may be attributed to the growth-regulating action of an increased level of activated TGF-beta 1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transforming growth factor-beta 1 synthesis in human thyroid follicular cells: differential effects of iodide and plasminogen on the production of latent and active peptide forms. 801

Transforming growth factor-beta 1 is an important cytokine in the pathophysiology of liver fibrosis, stimulating the production of extracellular matrix. Whether this cytokine can also control the degradation of matrix proteins in liver cells has not been investigated. Because plasmin is an important protease for the degradation of matrix glycoproteins, we investigated whether sinusoidal endothelial liver cells could contribute to fibrosing liver disease through the modulation of plasmin-generating enzymes in response to transforming growth factor-beta 1. Sinusoidal endothelial cells from guinea pig liver were investigated in pure monolayer culture. Using 125I-labelled transforming growth factor-beta, we demonstrated high-affinity binding sites on sinusoidal endothelial cells at a density of 9.3 x 10(2) per cell, and a dissociation constant of about 5.5 x 10(-11) mol/L. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the known three classes of membrane receptors for transforming growth factor-beta. Using biosynthetic labeling of proteins with 35S-methionine, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we showed that sinusoidal endothelial cells produce and secrete plasminogen activator inhibitor type 1 from the beginning of culture. Treatment of confluent cell cultures for 24 hr with transforming growth factor-beta 1 increased synthesis and release of plasminogen activator inhibitor type 1. The response was almost maximal at a concentration of 1 ng transforming growth factor-beta/ml and paralleled the increased synthesis of fibronectin. On reverse fibrin autography we proved that transforming growth factor-beta 1 stimulated the release of functionally active plasminogen activator inhibitor type 1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of sinusoidal endothelial liver cells to liver fibrosis: expression of transforming growth factor-beta 1 receptors and modulation of plasmin-generating enzymes by transforming growth factor-beta 1. 840 70

Using a 3-dimensional fibrin gel model system simulating fibroplasia of wound repair, we investigated the interaction between keloid fibroblasts and fibrin matrix and compared it with that of normal fibroblasts. Normal skin fibroblasts caused fibrin gel degradation under serum-free conditions, whereas keloid fibroblasts did not cause microscopically detectable gel degradation. Fibrin gel degradation occurred through plasmin-mediated fibrinolysis, which was initiated by fibroblasts exhibited high uPA but low plasminogen activator inhibitor-1 (PAI-1) activities, and transforming growth factor-beta 1 prevented fibrinolysis of normal fibroblasts by upregulating PAI-1 while downregulating uPA activities. In contrast, keloid fibroblasts exhibited an intrinsically high level of PAI-1 and a low level of uPA. This change in the ratio of activator and inhibitor activities was attributed to altered fibrin degradation by keloid fibroblasts. The PAI-1 increase was also demonstrated at the RNA level by Northern analysis. In terms of the pivotal role of the plasmin/plasminogen activator system in matrix remodeling, the elevated PAI-1 level exhibited by keloid fibroblasts may have significant consequences not only in altered fibrin degradation, but also in subsequent repair steps that lead to keloids and fibrosis.
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PMID:Elevated levels of plasminogen activator inhibitor-1 may account for the altered fibrinolysis by keloid fibroblasts. 861 30


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