Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator inhibitor-1 (PAI-1) is a primary endogenous inhibitor of tissue-type plasminogen activator (t-PA). In this study, we examined the effects of oversulfated fucoidan (OSF) derivatives and heparin on lipopolysaccharide (LPS)-induced release of PAI-1 antigen from cultured human umbilical vein endothelial cells (HUVEC). Addition of LPS (10 micrograms/ml) enhanced the release of PAI-1 by HUVEC but not of t-PA antigen. At 18 h, a 2.4-fold increase in the extracellular PAI-1 level was observed. The increased PAI-1 level was reduced to control level by the simultaneous addition of 10 micrograms/ml of OSF or heparin. The suppressive effect of native fucoidan was negligible. We also examined the molecular size effect of OSF, using 10-20, 20-40, and 40-60 kDa fragments. The result indicated that these fragments were effective as well as the 100-130 kDa form of OSF, hence suggesting an important role of the degree of sulfation. Interleukin-1 beta (IL-1 beta) is a potent inducer of PAI-1 in cultured HUVEC. Heparin, OSF, and its fragments did not suppress the IL-1 beta-induced release of PAI-1 antigen. Treatment of HUVEC with heparitinase or monoclonal antibody against heparin sulfate proteoglycan (HSPG) resulted in a complete loss of its ability to enhance PAI-1 release in response to LPS stimulation, while the chondroitinase ABC treatment hardly affected the PAI-1 production. These results suggest that HSPG is involved in the initial binding of LPS to HUVEC. The suppressive effects of OSF and heparin on LPS-induced PAI-1 release may result from the inhibition of LPS binding to the cell surface HSPG.
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PMID:Oversulfated fucoidan and heparin suppress endotoxin induction of plasminogen activator inhibitor-1 in cultured human endothelial cells: their possible mechanism of action. 757 76

The vascular endothelium plays a pivotal role in regulating the hemostatic system. Various cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are known to perturb endothelial cells to reduce antithrombogenicity. On the other hand, blood flow has been shown to affect the endothelium to maintain its antithrombogenicity under some levels of shear stress in the laminar flow system. We examined the role of hemodynamic forces on the vascular system under cytokine stimulation using a cone-plate type viscometer. Treatment of endothelial cells with either IL-1 beta or TNF-alpha under static conditions increased PAI-1, vWF and prostacyclin release, while t-PA secretion was unchanged. When cells were exposed to steady shear stress of 0, 6, 12, 18 and 24 dyne/cm2, the release of t-PA, t-PA-PAI complex and prostacyclin elevated with the increase of shear stress intensity, while a gradual decrease of total PAI-1 secretion was observed and vWF secretion was unchanged. On the contrary, active PAI-1 secretion was significantly decreased under the shear stress of over 18 dyne/cm2. Interestingly, cytokines, which did not affect t-PA secretion of resting cells, increased the t-PA secretion and had an additive effect on prostacyclin secretion with shear stress under the shear stress of over 18 dyne/cm2. PAI-1 elevation induced by cytokines was markedly abolished under the same shear forces. No additive effect was observed in the secretion of vWF. Thus, shear stress attenuates the alteration of the balance in the fibrinolytic and coagulation system induced by cytokines. These findings clearly indicate that hemodynamic forces play a crucial role in regulating the hemostatic activity in vivo.
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PMID:[Effect of shear stress on hemostatic regulation in endothelium]. 784 84

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

Plasma interleukin-6 (IL-6) was higher in patients with disseminated intravascular coagulation (DIC) than in those without DIC. Levels of IL-1 beta and TNF alpha were also significantly higher in patients with DIC. Plasma IL-6 was highest in patients with underlying sepsis and was also high in those with advanced solid cancer. Levels were high in some patients with acute promyelocytic leukaemia and were significantly higher in patients with organ failure than in those without this complication. Plasma IL-6 was higher in DIC patients showing a poor response to therapy than in those with a good response. Incubation with IL-6 caused significant increases in tissue factor activity in mononuclear cells and release of plasminogen activator-1 antigen from human umbilical vein endothelial cells. As increases in IL-6 might give rise to hypercoagulable and hypofibrinolytic states, this may be a cause of DIC and be related to prognosis and organ failure.
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PMID:Increased plasma level of interleukin-6 in disseminated intravascular coagulation. 821 55

The interaction of endothelin-1 (ET-1) with either interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) on the release of tissue plasminogen activator antigen (t-PA:Ag) and plasminogen activator inhibitor-1 antigen (PAI-1:Ag) was investigated in a culture system of vascular endothelial cells derived from human umbilical vein. The t-PA:Ag release was significantly decreased by either IL-1 beta or TNF alpha; ET-1 intensified the suppressive effect of the cytokines. In contrast, PAI-1:Ag release was significantly increased by either IL-1 beta or TNF alpha; ET-1 significantly reduced the stimulatory effect of the cytokines. The data suggest that endothelial cell-mediated fibrinolysis may be modulated by ET-1.
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PMID:Modulation by endothelin-1 of tissue plasminogen activator and plasminogen activator inhibitor-1 release from cultured human vascular endothelial cells: interaction of endothelin-1 with cytokines. 840 9

Tissue remodeling that accompanies ovarian follicular cell proliferation and migration during follicular maturation and ovulation involves enzymatic degradation of extracellular matrix by proteases such as plasminogen activator (PA). However, the potential role of interleukin-1 beta (IL-1 beta) in the regulation of the rat granulosa cell PA system during folliculogenesis is not known. In vitro treatment of both undifferentiated and differentiated granulosa cells with FSH (400 ng/ml) elicited a significant increase in secreted (PAs) and cell-associated (PAc) PA activities, which were inhibited by IL-1 beta (0.5-50 ng/ml) in a concentration- and time-dependent manner. Basal PAs and PAc activities were stimulated in cultures of undifferentiated granulosa cells by IL-1 beta but attenuated in differentiated ones. The inhibitory effect of IL-1 beta was accompanied by an increase in PA inhibitor (PAI) activity irrespective of the stage of follicular development. Both urokinase-type PA (uPA; 30 kDa) and tissue-type PA (tPA; 55 KDa) activities were present in cultures of undifferentiated granulosa cells, but only tPA was detectable in differentiated granulosa cell cultures. Activity of both enzymes was stimulated by FSH but inhibited by the cytokine in vitro. Whereas FSH-induced differentiation of granulosa cells as indicated by an increase in progesterone (P) secretion was attenuated by IL-1 beta irrespective of the cytodifferentiative state of granulosa cells, the inhibitory effect of gonadotropin on DNA synthesis was reversed by the cytokine at both stages of follicular maturation. These findings suggest that during ovarian folliculogenesis, IL-1 beta may modulate the progression of granulosa cells from a proliferative to a differentiated state and may play a control role in determining the fate of the follicle (i.e., ovulation vs. atresia).
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PMID:Regulation of rat granulosa cell plasminogen activator system: influence of interleukin-1 beta and ovarian follicular development. 856 85

Vascular endothelium is involved in both active and passive processes in haemostasis, but inflammatory cytokines such as interleukin 1 (IL-1) and tumour necrosis factor (TNF) have been reported to convert the comparatively inert endothelial cell to an inflammatory state. Acidic fibroblast growth factor (aFGF) in the presence of heparin has effects opposite to IL-1 on cultured human umbilical vein endothelial cells (HUVEC); therefore, we have investigated the modulation of IL-1-induced effects by the c combination of aFGF and heparin (aFGF/heparin). First passage HUVEC were cultured for 6 days in the presence of 20% human serum with and without the addition of 625 pM human recombinant aFGF (hr aFGF) and 7 microM heparin. On day 5, recombinant IL-1 beta was included for 24 h. The following day the cells were washed and measurements made of the release of prostacyclin, von Willebrand factor, plasminogen activator inhibitor type 1, and thrombospondin, both in the resting state and following stimulation for 60 min with 1 U/ml thrombin. Tissue-type plasminogen activator was assayed in HUVEC lysates. Similar experiments were performed to assess effects on the expression of vascular adhesion molecule, intracellular adhesion molecule, and E-selectin using an ELISA on cells in situ. This study indicates that aFGF/heparin in the culture medium of HUVEC abrogates the measured responses to IL-1. These data imply that routine endothelial cell culture with aFGF/heparin may cause artefacts, the effects of FGF and Il-1 may involve common pathways, and FGF/heparin may offer an approach to design therapeutics to counter the adverse effects of IL-1.
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PMID:Fibroblast growth factor and heparin protect endothelial cells from the effects of interleukin 1. 861 63

The plasmid pMK16 containing-SV40 replicated origin defective gene was efficiently introduced into early-passage human umbilical vein endothelial cells (HUVEC) using positively charged liposomes. The resulting cell line acquired an almost infinite lifespan, was morphologically unchanged, expressed SV40-antigen, and coexpressed von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), angiotensin conversion enzyme (ACE), and endothelin converting enzyme (ECE). In addition, these are the first immortalized human endothelial cells, to our knowledge, that biosynthesized and secreted interleukins (IL-1 beta and IL-6) in both a constitutive and regulated fashion and endothelin-1 (ET-1), the most potent vasoactive peptide, which has been suggested to be implicated in the pathogenesis of hypertension. Interestingly enough, both of the immortalized cells and the early-passage HUVEC from which the immortalized cells were obtained biosynthesized and secreted the same levels of ET-1 suggesting full maintenance of its biosynthetic pathway including the presence of active ECE, which cleaves big endothelin-1 (big-ET-1) to ET-1 and regulation factors. Moreover, the immortalized cells retained the ability to express the functional specific amino acid Na(+)-independent system Y+ transporter, which mediates L-arginine transport into endothelial cells from which endothelium-derived relaxing factor (EDRF, nitric oxide) is formed via the action of nitric oxide-synthase. Obtaining these immortalized human endothelial cells without alteration of the differentiated characteristics constitutes a useful model: (a) to study ET-1 secretion, gene regulation, and human ECE, which may be an important therapeutic target in disease conditions in which ET-1 is to be implicated; (b) to study L-arginine transport, which is a key step in the formation of EDRF; (c) to study IL-1 beta and IL-6 secretions, and gene regulations; (d) to substitute large quantities of HUVEC; and, finally, (e) to reproduce, starting with different primary endothelial cells both from human and animal origin.
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PMID:Establishment of permanent human endothelial cells achieved by transfection with SV40 large T antigen that retain typical phenotypical and functional characteristics. 883 14

Human keratinocytes synthesize and secrete tissue-type plasminogen activator (tPA). tPA converts the inactive precursor enzyme plasminogen into the trypsin-like proteinase plasmin. tPA is not found in normal epidermis, but in lesional epidermis from patients with a variety of cutaneous diseases, including psoriasis, pemphigus and pemphigoid. The presence of tPA is probably a reaction to the disease process rather than the initiating event in these etiologically and histopathologically diverse lesions. However, the factor(s) that upregulate tPA expression and secretion in keratinocytes have remained largely elusive. We sought to determine whether the inflammatory cytokine interleukin-1 beta (IL-1 beta), which is commonly present in diverse epidermal lesions, influences tPA production. Accordingly, we studied the influence of IL-1 beta on secretion of tPA by cells of the human keratinocyte cell line HaCaT. We found that IL-1 beta increased tPA secretion in these cells. Given the observation that IL-1 beta is a common proinflammatory mediator in cutaneous diseases, our findings may explain the increase in tPA in clinically and etiologically diverse inflammatory epidermal lesions.
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PMID:Interleukin-1 beta upregulates tissue-type plasminogen activator in a keratinocyte cell line (HaCaT). 887 52

The relative distribution of urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) was studied in cultured human gingival fibroblasts, healthy gingival tissues and inflamed gingival tissues by immunohistochemistry. In cultured gingival fibroblasts t-PA, u-PA and PAI-1 were expressed in cytoplasm; u-PA and PAI-1 were more intensely stained than t-PA; PAI-2 was not detectable in gingival fibroblasts. Following interleukin 1 beta (IL-1 beta) stimulation, the intensity of intracellular staining for t-PA was increased and a number of cells staining strongly for PAI-2 were seen; no difference in the intensity of immunostaining level was noted for the expression of u-PA and PAI-1 between IL-1 beta stimulated cells and unstimulated cells. In healthy gingival tissues, u-PA and PAI-1 displayed a wide distribution throughout all the connective tissue and epithelium; t-PA localized mainly in the connective tissue while PAI-2 showed little association with the connective tissue but did faintly stain in the epithelial layer. In inflamed gingival tissues, staining for t-PA was significantly increased in the extracellular matrix of the connective tissue, whereas staining for u-PA, PAI-1 and PAI-2 was found to be slightly increased, but no significant difference was noted for staining when compared with the healthy gingival tissues. A granular distribution of t-PA, u-PA, PAI-1 and PAI-2 was noted around areas of inflammatory cell infiltration. These immunohistochemical findings indicate that the plasminogen activator system produced by fibroblasts may be influenced by the presence of the inflammatory mediator IL-1 beta. In addition, the significant increase of t-PA in inflamed connective tissue and the wide expression of these components around inflamed cells may contribute to connective tissue degradation and may relate to the migration and localization of monocytes/macrophages in inflamed tissue.
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PMID:Immunohistochemical demonstration of the plasminogen activator system in human gingival tissues and gingival fibroblasts. 952 17


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