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

Stimulated human monocytes release several proteins thought to play a role in inflammation, including interleukin 1, tumor necrosis factor, and plasminogen activator. We have purified another proinflammatory protein that is chemotactic for human neutrophils from conditioned medium of lipopolysaccharide-stimulated monocytes. After a series of steps that included anion-exchange chromatography, gel filtration, and HPLC on cation-exchange and reverse-phase columns, an apparently pure protein was obtained that migrated as a single 7-kDa band on NaDodSO4/polyacrylamide gels under reducing or nonreducing conditions. The amino acid composition of this monocyte-derived neutrophil chemotactic factor was different from that of interleukin 1 and tumor necrosis factor. N-terminal amino acid sequence of the first 42 residues was determined. This portion of the molecule has up to 56% sequence similarity with several proteins that may be involved in host responses to infection or tissue injury. It is identical to a portion of a sequence deduced from an mRNA induced by staphylococcal enterotoxin treatment of human leukocytes. At the optimal concentration of 10 nM, 50% of neutrophils added to chemotaxis assay wells migrated toward the pure attractant. Potency and efficacy are comparable to that of fMet-Leu-Phe, which is often used as a reference. In contrast to many attractants, the protein was not chemotactic for human monocytes.
 ...
PMID:Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. 348 May 40

Migration of astrocytes is thought to play a role in nerve regeneration and to be mediated, at least in part, by inflammation-associated cytokines. Plasminogen activators are secreted proteases that function in fibrinolysis and participate in cellular migration and invasion and, in some cases, are modulated by cytokines. Here, we show that two cytokines, tumor necrosis factor-alpha and interleukin-1 beta, can modulate plasminogen activation in astrocytes, each causing 90% reduction of total plasminogen activator activity. Direct and reverse zymography indicated that this reduction resulted from two simultaneous events, a pronounced decrease in tissue-type plasminogen activator activity and an induction of plasminogen activator inhibitor-1. Northern hybridization analysis indicated a 30-fold increase of the steady-state level of plasminogen activator inhibitor-1 mRNA following treatment with each of the two cytokines. Both of the cytokine-induced effects could be blocked by cycloheximide or actinomycin D. When signal transduction pathways were blocked, the results indicated the involvement of reduction in cyclic AMP levels, protein kinase activity, and arachidonic metabolites of the lipoxygenase pathway. The results thus show that the two cytokines reduce the ability of astrocytes to conduct fibrinolysis and extracellular proteolysis, and suggest that the effect of these cytokines on members of the plasminogen activation system is through a common signal transduction pathway.
 ...
PMID:Components of the plasminogen activator system in astrocytes are modulated by tumor necrosis factor-alpha and interleukin-1 beta through similar signal transduction pathways. 756 46

Administration of low doses endotoxin or tumor necrosis factor (TNF) in human experimental models for sepsis results in transient activation of both coagulation and fibrinolysis and subsequent inhibition of the fibrinolytic system by plasminogen activator inhibitor type 1 (PAI-1). We have investigated in a baboon model for sepsis, whether administration of a lethal or sublethal dose of living E. coli could induce similar activation patterns. Levels of thrombin-antithrombin III (TAT) complexes increased significantly to zeniths of 425 and 33 times the baseline values at t+360 in the lethal and sublethal group, respectively. Activation of fibrinolysis, as reflected by plasmin-alpha 2 antiplasmin (PAP) complexes, in the sublethal group was maximal at t+60 and was increasingly inhibited thereafter in spite of a sustained increase of tissue type plasminogen activator (t-PA) levels. In the lethal group PAP complexes increased to a zenith of 38 times the baseline values at t+240. PAI-1 levels increased to 15 times the baseline values at t+360 in the sublethal group, whereas in the lethal group they increased almost linearly to 20 times the baseline values at t+360. Despite high levels of PAI-1, effective inhibition of the fibrinolysis was not established until at T+240 in the lethal group. The difference in activation patterns of both mediator systems in the sublethal and lethal group of baboons indicate that extensive activation of coagulation contributes to the lethal complications in sepsis.
 ...
PMID:Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. 768 56

The fibrinolytic potential of the endothelial cells gives important antithrombotic properties to the vascular wall. Thrombosis is a frequent complication to atherosclerosis and other conditions where inflammatory mediators are present in the vascular wall. Inflammatory agents like lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF alpha) have been demonstrated to modulate the expression of fibrinolytic factors in cultured endothelial cells. In the present study the expression of tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) antigen in conditioned medium from cultured human umbilical vein (HUVEC) and human saphenous vein (HSVEC) endothelial cells was investigated under basal conditions and after stimulation with LPS, TNF alpha, interferon-gamma (IFN-gamma) or interleukin-6 (IL-6) alone or in combinations. Stimulation with LPS or TNF alpha increased the expression of PAI-1, u-PA and PAI-2 in HUVEC and HSVEC, while the t-PA response differed between the two cell types. The effects of TNF alpha were modulated by IFN-gamma but not by IL-6. The increased expression of u-PA after stimulation with TNF alpha was reduced by IFN-gamma. In contrast, TNF alpha-induced expression of PAI-2 was synergistically increased by addition of IFN-gamma. These effects of IFN-gamma represent additional mechanisms by which inflammatory mediators may turn the fibrinolytic potential of the endothelium in a prothrombotic direction.
 ...
PMID:Interferon-gamma modulates the fibrinolytic response in cultured human endothelial cells. 777 58

The objective of the present in vitro study was to examine the potential modulatory influence of tumor necrosis factor-alpha (TNF alpha) on the granulosa cell plasminogen activator (PA) system during follicular development. Undifferentiated and differentiated rat granulosa cells of preantral follicles and antral follicles, respectively, were cultured in a chemically defined medium with or without TNF alpha and in the absence or presence of FSH (400 ng/ml). TNF alpha (0.5-50 ng/ml) inhibited basal and FSH-induced net PA activities in cultures of granulosa cells from preantral and antral follicles in a concentration- and time-dependent manner. Although PA activities with corresponding molecular masses of 55 kDa and 30 kDa (tissue-[tPA] and urokinase-[uPA] type PA, respectively) were observed in culture of undifferentiated granulosa cells, only tPA was detectable in differentiated cells. Concomitant to the stimulation in PA activities by FSH was a marked increase in progestin secretion and a decrease in DNA synthetic capacity at both stages of follicular development. Independent of the differentiative state of the granulosa cells, TNF alpha suppressed FSH-stimulated tPA activity, but potentiated FSH-induced uPA activity in undifferentiated granulosa cells. The inhibition of the gonadotropin action by TNF alpha was accompanied by an increase in PA inhibitor activity, which was more pronounced in cultures of differentiated granulosa cells. TNF alpha inhibited FSH-induced progestin secretion and reversed the action of the gonadotropin on DNA synthesis irrespective of stage of follicular maturation. These studies demonstrate that TNF alpha modulates gonadotropic action on granulosa cell differentiation (PA and progestin secretion) and proliferation (DNA synthesis) during follicular development.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Tumor necrosis factor alpha inhibits rat granulosa cell plasminogen activator activity in vitro during follicular development. 777 96

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.
 ...
PMID:Effects of TGF-beta and TNF-alpha on procoagulant and fibrinolytic pathways of human tracheal epithelial cells. 781 Jun 74

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.
 ...
PMID:[Effect of shear stress on hemostatic regulation in endothelium]. 784 84

We measured serum levels of endotoxin, cytokines, and eicosanoids and investigated their relationship to serum complement levels in patients with sepsis. Serum endotoxin (Et) levels (5.3 +/- 2.4 pg/ml) were within the normal range, but levels of tumor necrosis factor-alpha (TNF-alpha, 114 +/- 104.94 pg/ml), interleukin 6 (IL-6, 86.7 +/- 50.9 pg/ml), interleukin 8 (IL-8, 86.8 +/- 49.7 pg/ml), type-II phospholipase A2 (type II PLA2, 211.3 +/- 193.9 ng/ml), leukotriene B4 (LTB4, 88.7 +/- 27.2 pg/ml), thromboxane B2 (TXB2, 58.7 +/- 50.9 pg/ml) and 6-keto-prostaglandin F1 alpha (PGF1 alpha, 21.0 +/- 11.0 pg/ml) levels were above normal. Levels of C3a (1088.4 +/- 83.8.7 ng/ml) and C4a (1951.5 +/- 1697.8 ng/ml) were also above normal; C3 (66.0 +/- 25.6 mg/dl) and C4 (23.6 +/- 5.3 mg/dl) were within the normal range, and C5a was lower than the detectable limit in all but one of the subjects. Serum TNF-alpha was significantly correlated with C3a (p < 0.001). Serum IL-6 had a significant negative correlation with C3 (p = 0.002) and C4 (p = 0.010). Type II PLA2 was significantly correlated with C3a (p < 0.001). There were no significant correlations between serum Et or IL-8 and serum C3, C4, C3a or C4a. Our findings suggest that increased levels of TNF-alpha, IL-6, and Type II PLA/ in patients with sepsis contribute to activation of the complement system.
 ...
PMID:Blood cytokine and complement levels in patients with sepsis. 793 3

Fibrinolytic parameters and von Willebrand factor (vWF) antigen were measured in the plasma of 10 patients with hemolytic uremic syndrome (HUS). Samples were taken at presentation and again 2 wk later, before and after infusion of 1-desamino-8-arginine vasopressin. Compared with the plasma values of healthy control children, levels of tissue-plasminogen activator (t-PA) antigen, plasminogen activator inhibitor type I (PAI-1) activity, and vWF as well as fibrin(ogen) degradation products were significantly elevated in the plasma of HUS patients on admission. No response of the fibrinolytic parameters and vWF were seen when 1-desamino-8-arginine vasopressin infusion was given on admission. After 2 wk, t-PA antigen and vWF had partially returned to basal values, and t-PA antigen increased rapidly again after 1-desamino-8-arginine vasopressin infusion. To investigate whether verocytotoxin contributes to the alteration of the fibrinolytic system found in HUS patients, purified verocytotoxin-1 (VT-1) was added to the media of cultured human endothelial cells. Addition of VT-1 alone did not change the production of t-PA, plasminogen activator inhibitor type I, and vWF antigen in these cells. However, when the endothelial cells were preincubated with tumor necrosis factor-alpha to increase the number of VT-1 receptors, VT-1 induced a marked decrease of the synthesis of t-PA, plasminogen activator inhibitor type I, and vWF. This was caused by a decrease in overall protein synthesis in the tumor necrosis factor-alpha- and VT-1-treated endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The fibrinolytic system in the hemolytic uremic syndrome: in vivo and in vitro studies. 797 Sep 42

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.
 ...
PMID:Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents. 802 Aug 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>