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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated immunohistochemically the localization of urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), plasmin inhibitor (PI), and transforming growth factor-beta (TGA-beta) in tissue sections to examine the relationships between their localization and local invasiveness, tumor size and cervical lymph node metastasis of head and neck squamous cell carcinomas (SCCs). In invasive carcinomas, u-PA, PAI-1 and PI were stained stronger in carcinoma cells than in surrounding connective tissues or normal epithelial cells. However, no relationship was found between cell invasiveness and the localization of t-PA and TGF-beta in invasive SCCs. The expression of these factors was not related to cervical lymph node metastasis or the size of head and neck SCCs. These results suggest a disorder of the fibrinolytic systems of carcinoma cells, and that u-PA play a part in the invasion of head and neck SCCs by degenerating connective tissue.
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PMID:[Immunohistological study of fibrinolytic factors of head and neck squamous cell carcinomas]. 770 77

In the present study, we have examined the influence of transforming growth factor-alpha (TGF alpha) and FSH in vitro on the granulosa cell plasminogen activator (PA) system accompanying cell proliferation and differentiation during follicular development. Undifferentiated and differentiated rat granulosa cells from diethylstilbestrol (DES)- and eCG-treated immature rats, respectively, were cultured in medium containing FSH (400 ng/ml), TGF alpha (0.5-50 ng/ml), and/or transforming growth factor-beta (TGF beta; 25-100 ng/ml). Net secreted PA (PAs) and cell-associated PA (PAc) activities were higher in differentiated cells and were stimulated by TGF alpha (but not by TGF beta) in a concentration-dependent manner. Basal and FSH-stimulated PAs was higher than PAc and accounted for 70-80% of the total PA activity in both cell preparations. FSH-stimulated PA activities increased in undifferentiated granulosa cells but decreased in differentiated cells with increased duration of culture. A biphasic effect (stimulatory in the first 24 h and inhibitory thereafter) of TGF alpha on FSH-induced PA activities was observed in the cultures of undifferentiated granulosa cells. Whereas both urokinase (uPA) and tissue (tPA) PA appeared to be present in cultures of granulosa cells from DES-treated rats, only tPA could be detected in those from eCG-treated animals. TGF alpha increased basal tPA activity at both stages of follicular development but inhibited activities of uPA in undifferentiated granulosa cells, irrespective of the presence of FSH. This growth factor stimulated basal progesterone (P) and 20 alpha-dihydroprogesterone (20 alpha-OH-P) secretion (an index of granulosa cell differentiation), the effect being more pronounced at the late stage of follicular development.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Follicular stage-dependent regulation of rat granulosa cell plasminogen activator system by transforming growth factor-alpha in vitro. 771 Dec 10

The epithelial lining of the airways is subject to injury through several processes, including infections, bronchiolitis, and fume exposures. Because airway fibrin deposition influences the course of local injury, we examined how two inflammatory cytokines influenced fibrin formation and clearance in human tracheal epithelial cells (TEC). TEC were treated with transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha). TNF-alpha increased release of tissue factor (TF)-related procoagulant activity that, through generation of factor Xa, promotes assembly of the prothrombinase complex at the cell surface. Fibrinolytic activity was plasminogen dependent and due to both urokinase (uPA) and tissue plasminogen activator (tPA). The cells expressed plasminogen activator inhibitor 1 (PAI-1), but relatively little PAI-2. Depression of fibrinolysis by TGF-beta correlated with increased PAI-1. Conversely, TNF-alpha increased plasminogen activator (PA) activity due to increased uPA. Fibrinolytic activity was inhibited by actinomycin D and cyclohexamide, but changes in mRNAs for uPA, tPA, PAI-1, and TF by either cytokine were not appreciable. PAI-2 mRNA was not found. The data indicate that TGF-beta decreases the fibrinolytic capacity of TEC, suggesting that this cytokine promotes fibrin retention. TNF-alpha increases expression of both procoagulant and fibrinolytic activities; this differential regulation could favor both pericellular fibrin formation and dissolution.
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PMID:Effects of TGF-beta and TNF-alpha on procoagulant and fibrinolytic pathways of human tracheal epithelial cells. 781 Jun 74

Human omental microvascular endothelial (HOME) cells seeded on Matrigel begin to migrate within 1 h, forming honeycomb-like structures and capillary-like networks within 18 h. Cross-sections of the capillary networks show them to be tube-like structures. Northern blot analysis showed that tissue-type plasminogen activator (t-PA) mRNA synthesis increased from the initial state at 0 h after seeding on Matrigel, reaching a steady state after 4 h. This elevated cellular t-PA mRNA level decreased markedly at 24 h. In contrast, the cellular plasminogen activator inhibitor-1 (PAI-1) mRNA level demonstrated biphasic curves during the 24 h after seeding on Matrigel: the PAI-1 mRNA level was increased eightfold initially at 4 h over that at 0 h, then declined, and again secondarily increased to greater than tenfold at 18 h. Cellular levels of both 72 kD type IV collagenase and tissue inhibitor of metalloproteinase (TIMP-2) mRNA were increased only a slightly within 2-4 h. These elevated mRNA levels were maintained for 18 h, while the TIMP-1 mRNA level increased up to 18 h, reaching around three times the level at 0 h. However, on collagen-coated dishes, cellular levels of t-PA, PAI-1, 72 kD type IV collagenase, TIMP-1, and TIMP-2 mRNA were not greatly changed during incubation for 24 h. On Matrigel, the cellular t-PA mRNA level at 18 h after seeding was greatly increased when treated with specific anti-transforming growth factor-beta (TGF-beta) antibody. In contrast, both PAI-1 and TIMP-1 mRNA levels at 18 h were reduced in the presence of anti-TGF-beta antibody. Development of the capillary network on Matrigel was inhibited in the presence of anti-t-PA antibody. Epidermal growth factor (EGF) enhanced t-PA gene expression and TGF-beta inhibited its expression in HOME cells cultured on collagen-coated dishes. On the other hand, TGF-beta enhanced cellular expression of the PAI-1 gene. The formation of a capillary network by HOME cells on Matrigel appears to be balanced by angiogenic EGF and anti-angiogenic TGF-beta through modulation of PA activity.
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PMID:Expression of tissue-type plasminogen activator and its inhibitor couples with development of capillary network by human microvascular endothelial cells on Matrigel. 782 31

We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology.
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PMID:Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents. 802 Aug 88

Recombinant human cytokines were examined for their effects on plasminogen activator inhibitor-1 (PAI-1) production by human articular cartilage and chondrocyte monolayer cultures. Cartilage and chondrocytes were cultured with and without added cytokines and the conditioned media assayed for PAI-1 by a specific enzyme-linked immunosorbent assay, and mRNA levels determined by Northern blot analysis. Tumor necrosis factor alpha (TNF alpha) reduced, and transforming growth factor-beta (TGF-beta) and basic fibroblast growth factor (bFGF) increased, the levels of PAI-1 antigen and mRNA in the culture fluids and cell extracts, respectively. The effects of TNF alpha and TGF-beta on PAI-1 antigen levels were both time- and concentration-dependent; optimum doses being 10-100 pM TNF alpha and 0.4-0.8 nM TGF-beta, with each cytokine exerting its effect on PAI-1 antigen levels within 8 h of addition to culture. TNF alpha (and interleukin-1 alpha) also countered the effects of TGF-beta and bFGF. The anti-inflammatory drugs, indomethacin and dexamethasone, did not appear to modulate PAI-1 levels in cultures of cartilage tissue. The inhibition of PAI-1 levels by cytokines and reagents which stimulate cartilage resorption (i.e., TNF alpha, interleukin-1 alpha, retinoic acid) and enhancement by cytokines which counter it (i.e., TGF-beta, bFGF) further implicate plasminogen activator in the mechanism(s) of cartilage degradation in diseases such as arthritis.
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PMID:Cytokine modulation of plasminogen activator inhibitor-1 (PAI-1) production by human articular cartilage and chondrocytes. Down-regulation by tumor necrosis factor alpha and up-regulation by transforming growth factor-B basic fibroblast growth factor. 805 59

A hitherto unknown function for transglutaminase (TGase; R-glutaminyl-peptide: amine gamma-glutamyltransferase, EC 2.3.2.13) was found in the conversion of latent transforming growth factor-beta (LTGF-beta) to active TGF-beta by bovine aortic endothelial cells (BAECs). The cell-associated, plasmin-mediated activation of LTGF-beta to TGF-beta induced either by treatment of BAECs with retinoids or by cocultures of BAECs and bovine smooth muscle cells (BSMCs) was blocked by seven different inhibitors of TGase as well as a neutralizing antibody to bovine endothelial cell type II TGase. Control experiments indicated that TGase inhibitors and/or a neutralizing antibody to TGase did not interfere with the direct action of TGF-beta, the release of LTGF-beta from cells, or the activation of LTGF-beta by plasmin or by transient acidification. After treatment with retinoids, BAECs expressed increased levels of TGase coordinate with the generation of TGF-beta, whereas BSMCs and bovine embryonic skin fibroblasts, which did not activate LTGF-beta after treatment with retinoids, did not. Furthermore, both TGase inhibitors and a neutralizing antibody to TGase potentiated the effect of retinol in enhancing plasminogen activator (PA) levels in cultures of BAECs by suppressing the TGF-beta-mediated enhancement of PA inhibitor-1 (PAI-1) expression. These results indicate that type II TGase is a component required for cell surface, plasmin-mediated LTGF-beta activation process and that increased expression of TGase accompanies retinoid-induced activation of LTGF-beta.
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PMID:Requirement for transglutaminase in the activation of latent transforming growth factor-beta in bovine endothelial cells. 809 47

In established normal rat kidney (NRK) cells, synthesis of the 52 kDa type-1 inhibitor of plasminogen activator [p52(PAI-1)] is stimulated by the cell shape-modulating fungal metabolite cytochalasin D (CD). Induction paralleled the time course of morphologic change and reflected relatively specific increases in saponin-resistant p52(PAI-1) protein accumulation (approximating ten- to thirty-fold over control) and mRNA abundance (seven- to nine-fold). Augmented p52 (PAI-1) mRNA levels closely correlated with increases in 43 kDa p52(PAI-1) core protein biosynthesis. Sensitivity to tunicamycin indicated that N-linked post-translational modifications to this 43 kDa core species generated the full complement of 50 kDa (intermediate) and 52 kDa (mature) p52(PAI-1) glycosylated isoforms. CD-induced p52(PAI-1) expression occurred efficiently in quiescent NRK cells maintained under serum-free conditions as well as in fully serum-supplemented actively growing cultures. While 8-bromo-cAMP reduced both constitutive and transforming growth factor-beta-induced p52(PAI-1) synthesis by > 50%, no such inhibition was evident in short-term (4 h) CD-stimulated cultures. Long-term (24 h) exposure of NRK/CD cells to 8-bromo-cAMP did result in an approximately 34% reduction in stimulated p52(PAI-1) expression, however, levels expressed by NRK/CD+cAMP populations remained markedly elevated relative to control values. These data suggest the existence of a cell shape-dependent aspect of p52(PAI-1) expression control distinct from both the constitutive and growth factor-mediated pathways of gene regulation.
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PMID:Induced expression of p52(PAI-1) in normal rat kidney cells by the microfilament-disrupting agent cytochalasin D. 813 87

Vitamin D3, 1 alpha,25(OH)2D3, and its metabolites regulate the growth and differentiation of several cell types. Vitamin D3 and its analogue, calcipotriol (MC 903), inhibit the proliferation of cultured human and mouse keratinocytes and induce keratinocyte differentiation. Calcipotriol is effective in the treatment of psoriasis in which increased plasminogen activator activity has been reported. We analyzed therefore the effects of calcipotriol and vitamin D3 on the production of plasminogen activator (PA) activity in human keratinocytes and a mouse keratinocyte cell line. Caseinolysis-in-agarose assays indicated that vitamin D3 decreases total PA activity in both keratinocyte culture systems. Zymographic analyses of the medium indicated that the secreted activator was of the urokinase type (u-PA). A decrease was observed also in extracellular matrix and membrane-associated u-PA activity of vitamin D3 and calcipotriol treated cells. Immunoblotting analysis of the conditioned medium from human keratinocytes revealed a decrease in the u-PA protein levels. Accordingly, Northern hybridization analysis of the respective mRNAs indicated a rapid decrease in urokinase mRNA levels. Calcipotriol decreased u-PA activity also in the presence of inducers of u-PA activity like transforming growth factor-beta, epidermal growth factor, and phorbol-12-myristate-13-acetate. Calcipotriol also caused a decrease in tissue type PA (t-PA) activity of the keratinocytes. Most t-PA activity was associated with the extracellular matrices and cell membranes as revealed by zymographic analysis. Paradoxically, the secretion and deposition of the matrix of plasminogen activator inhibitor type 1 decreased in calcipotriol-treated cells. The results indicate that a major effect of vitamin D3 on cultured keratinocytes is a decrease of plasminogen activator activity.
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PMID:Vitamin D3 and calcipotriol decrease extracellular plasminogen activator activity in cultured keratinocytes. 822 32

The capacity of macrophages to influence directly and indirectly fibrinolytic processes in atherosclerosis was studied using macrophages isolated from atherosclerotic plaques of patients undergoing surgical repair of distal aortic and femoral arteries. These cells were characterized by their morphology, adherence, esterase positivity, and expression of CD14 antigen. Production of plasminogen activator inhibitor type-1 (PAI-1) by plaque macrophages (6.7 +/- 2.7 ng/10(5) cells/24 hours [mean +/- SEM]) was significantly greater than PAI-1 production by blood monocytes isolated simultaneously from the same patients (1.8 +/- 1.5 ng/10(5) cells/24 hours). Production of tissue type plasminogen activator and urokinase type was not augmented compared to blood monocytes. Conditioned medium from cultured plaque macrophages significantly increased production of PAI-1 by endothelial cells (85 +/- 11% above basal) and vascular smooth muscle cells (25 +/- 10%) in vitro. This response was significantly greater than the response to monocyte-conditioned medium (endothelial cells 38 +/- 11%, vascular smooth muscle cells 2.5 +/- 2.0%). Stimulation of endothelial cell PAI-1 production by macrophage-conditioned medium was partially inhibitable by a monoclonal antibody to transforming growth factor-beta. Tissue type plasminogen activator production by endothelial cells and vascular smooth muscle cells was not affected by plaque macrophage- or monocyte-conditioned medium. Urokinase type plasminogen activator production by endothelial cells and vascular smooth muscle cells was undetectable in control medium and was augmented to similar levels in response to plaque macrophage- and monocyte-conditioned media. These results demonstrate upregulation of PAI-1 production by macrophages in atheromatous plaques and the capacity of soluble products from plaque macrophages to upregulate PAI-1 production by endothelial cells and vascular smooth muscle cells in vitro. These data suggest that macrophages in atherosclerotic plaques may inhibit thrombolysis both directly and indirectly by effects of their soluble products on endothelial cells and vascular smooth muscle cells.
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PMID:Atheromatous plaque macrophages produce plasminogen activator inhibitor type-1 and stimulate its production by endothelial cells and vascular smooth muscle cells. 836 83


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