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)

Agents such as retinol, interleukin 1 and catabolin stimulate resorption of cultured cartilage. This process seems to be mediated by chondrocytes, but the mechanism by which breakdown occurs remains unknown. We have found that (10(-6)-10(-8) M) retinoic acid and (1 X 10(-6) M) retinol, in the presence or absence of a factor derived from cultured synovium (synovial factor), stimulate the degradation of fibrin by human chondrocytes in culture. Plasminogen was required for the enhancement of fibrinolysis, suggesting that the breakdown depended upon the production of plasminogen activators and subsequent liberation of plasmin. However, the chondrocytes did not release significant amounts of plasminogen activator, and the effects of the synovial factor and retinoids resulted from augmentation of the production or activity of enzymes which remained bound to the cell layer. The role of plasminogen in the resorption of cultured cartilage was also investigated. In the presence of plasminogen, (1 X 10(-8) M) retinoic acid or synovial factor stimulated the breakdown of cultured bovine nasal cartilage, but in the absence of plasminogen, the effect of synovial factor was abolished and that of retinoic acid reduced. However, in cultures containing both retinoic acid and synovial factor the resorption process was not affected by removal of plasminogen. Thus, the resorption of cartilage matrix in vitro may be partially mediated by plasminogen activators and plasmin.
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PMID:Retinoids and synovial factor(s) stimulate the production of plasminogen activator by cultured human chondrocytes. A possible role for plasminogen activator in the resorption of cartilage in vitro. 391 88

Human synovial explants in culture release material that stimulates the production of prostaglandin E2 (PGE2) and several extracellular enzymes by human chondrocytes. Fractionation of conditioned medium by gel filtration revealed a protein of approx. 15 kDa, which in addition to stimulating production of PGE2 and plasminogen activator by human articular chondrocytes, possessed interleukin 1 activity and induced cartilage degradation. Further purification using iso-electric focussing again showed co-elution of these activities with a major pI of 6.9 and a minor pI of 5.1-5.3. This study indicated that human synovium releases a factor that is closely related to or identical with interleukin 1 and suggests that this protein may participate in cellular interactions that occur within the rheumatoid joint.
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PMID:Partial purification of a factor from human synovium that possesses interleukin 1, chondrocyte stimulating and catabolin-like activities. 391 34

The role that lipid uptake might play in macrophage activation was investigated using mouse peritoneal macrophages in vitro. Incubation with acetylated LDL for 48 hours resulted in a 12 fold increase in cholesterol ester content in macrophages; incubation with oxidized LDL resulted in a 6 fold increase in cholesterol ester, while incubation with native LDL did not result in cholesterol accumulation. Incubation of macrophages with acetylated LDL or oxidized LDL produced no change in macrophage production of plasminogen activator or secretion of interleukin 1 or superoxide anion.
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PMID:The effect of LDL and modified LDL on macrophage secretion products. 609 26

Group A streptococcal peptidoglycan has previously been shown to be arthritogenic in rats and has been implicated as a structure present in a class of possible etiologic agents for rheumatoid arthritis. The present study reports that conditioned medium from human monocytes, after interaction with cell wall sonicates of four group A streptococcal strains, stimulates the plasminogen activator (PA) activity of nonrheumatoid synovial fibroblasts. Low concentrations of N-acetylmuramyl-L-alanyl-D isoglutamine (muramyl dipeptide) can also generate this synovial activator (SA) activity from human monocytes. Preliminary biochemical data suggest that the SA activity is distinct from interferon-gamma, interleukin 1, and interleukin 2. These results indicate that agents that are arthritogenic in rats can modulate human synovial fibroblast functions via monocytes. The findings are proposed to have possible significance for an understanding of the cellular interactions involved in the formation and function of the rheumatoid pannus, because PA has been invoked as possibly being generally important for the processes of cell migration, tissue remodeling, and inflammation.
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PMID:Streptococcal cell walls and synovial cell activation. Stimulation of synovial fibroblast plasminogen activator activity by monocytes treated with group A streptococcal cell wall sonicates and muramyl dipeptide. 680 90

Although studies with interleukin-1 receptor antagonist (IL-1ra) in animal models have shown that IL-1 contributes to mortality in sepsis, the mechanisms whereby IL-1 mediates lethal effects are not well established. A possible mechanism is that IL-1 enhances the activation and release of other inflammatory mediator systems such as coagulation, fibrinolysis, neutrophils, and secretory-type phospholipase A2 (sPLA2). We investigated this possibility by assessing the effect of intravenously injected recombinant human IL-1 alpha (rhIL-1 alpha) on these plasma parameters in baboons. In addition, we examined the course of these inflammatory parameters in baboons after a challenge with a lethal dose of Escherichia coli and while receiving a 24-hour constant infusion of IL-1ra or placebo. Intravenous administration of IL-1 alpha (10 micrograms/kg) induced the formation of thrombin, as evidenced by the appearance of thrombin-antithrombin III (TAT) complexes into the circulation (peak levels, 188 +/- 92 ng/mL at 2 hours), as well as the activation of fibrinolysis, assessed by circulating plasmin-alpha 2-antiplasmin complexes (PAP complexes; peak levels, 0.4% +/- 0.03% of fully activated plasma at 1 hour), the release of tissue-type plasminogen activator (t-PA; peak levels, 6 +/- 2 ng/mL at 2 hours), and its inhibitor, plasminogen activator inhibitor (PAI; peak levels, 724 +/- 246 ng/mL at 4 hours). Il-1 alpha administration also induced the release of sPLA2 (maximal levels, 336 +/- 185 ng/mL at 8 hours), but not degranulation of neutrophils. In the septic baboons, a significant reduction of the formation of thrombin (peak TAT levels decreased from 582 +/- 78 ng/mL to 219 +/- 106 ng/mL; P < .005), the release of t-PA (peak levels decreased from 37 +/- 11 ng/mL to 17 +/- 2 ng/mL; P < .001), and its inhibitor, PAI (peak levels decreased from 2,639 +/- 974 ng/mL to 1,110 +/- 153 ng/mL; P <.001), was observed in the group receiving IL-1ra compared to that receiving placebo. The release of neutrophilic elastase was also significantly attenuated in IL-1a-treated animals (peak levels, 1,024 +/- 393 and 655 +/- 104 ng/mL in control and treatment groups, respectively; P < .05). The difference between sPLA2 levels in both groups, although higher in the controls (maximal levels, 3,140 +/- 1,435 ng/mL in control v 2,217 +/- 1,375 ng/mL in IL-1ra-treated group), was not significant. Thus, IL-1 contributes to activation of various other mediator systems in severe sepsis in nonhuman primates. We propose that these effects may explain the lethal actions of IL-1 in this sepsis model and suggest a similar role for IL-1 in severe human sepsis.
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PMID:Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia. 762 Jan 56

Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. Since in aging and in atherosclerosis the changes observed in the endothelium resemble those of in vitro aged endothelial cells, we have examined the expression of PAI-1 in cells at different population doublings. In senescent endothelial cells, PAI-1 mRNA and protein are constitutively high, but uninducible by exogenous interleukin 1 alpha as well as by the phorbol ester TPA. Interestingly the increase of PAI-1 levels correlates with the upregulation of interleukin 1 alpha, which characterizes endothelial cell senescence. Since PAI-1 expression is not increased in young cells made nondividing by contact inhibition, we anticipate that PAI-1 expression can be used as an appropriate marker of endothelial senescence. Moreover, PAI-1 was not upregulated in senescent or in progeric human fibroblasts, which do not overexpress interleukin 1 alpha, thus suggesting that multiple pathways may exist to regulate aging of human fibroblasts and endothelial cells.
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PMID:Senescence-dependent regulation of type 1 plasminogen activator inhibitor in human vascular endothelial cells. 762 47

Pentoxifylline (oxpentifylline) is a methylxanthine derivative with potent hemorrheologic properties. In the United States it is marketed for the treatment of intermittent claudication. Human and animal studies have shown that pentoxifylline therapy results in a variety of physiological changes at the cellular level, which may be important in treating a diverse group of human afflictions. Immune modulation includes increased leukocyte deformability and chemotaxis, decreased endothelial leukocyte adhesion, decreased neutrophil degranulation and release of superoxides, decreased production of monocyte-derived tumor necrosis factor, decreased leukocyte responsiveness to interleukin 1 and tumor necrosis factor, inhibition of T and B lymphocyte activation, and decreased natural killer cell activity. Hypercoagulable states improve through decreased platelet aggregation and adhesion, increased plasminogen activator, increased plasmin, increased antithrombin III, decreased fibrinogen, decreased alpha 2-antiplasmin, decreased alpha 1-antitrypsin, and decreased alpha 2-macroglobulin. Wound healing and connective tissue disorders may respond to an increase in fibroblast collagenases and decreased collagen, fibronectin, and glycosaminoglycan production. Fibroblast responsiveness to tumor necrosis factor is also diminished. Potential medical uses of pentoxifylline are reviewed.
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PMID:Pentoxifylline. 860 73

The authors tested in vitro the effect of glucose-based and amino acid-based dialysate effluent on the function of human peritoneal mesothelial cells. After 9 days of exposure to the tested effluents with medium (1:1 v/v) or to a medium supplemented with 10% fetal calf serum (FCS) (control), several functional properties of the cells were studied. The synthesis of DNA measured by incorporation of 3H-methyl-thymidine was higher in mesothelial-cell monolayers exposed to the dialysates than in the controls. Synthesis of hyaluronic acid was similar in all three groups, but after stimulation with Il-1 the cells exposed to the dialysates produced more hyaluronic acid. Synthesis of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) was higher in the control cells. However, after stimulation with IL-1, the cells exposed to the dialysate showed greater synthesis of PAI-1 than of t-PA. Also, procoagulant activity of the control cells was higher than that of the cells exposed to the dialysates. We have concluded that the functional properties of the mesothelial cells may be altered in vitro during prolonged exposure to the dialysate, something that may also occur in vivo.
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PMID:Functional properties of mesothelial cells after prolonged exposure to dialysate effluent. 853 91

TNF-stimulated gene 6 (tsg6), encoding a 35-kDa secretory glycoprotein (TSG-6), is induced in fibroblasts, chondrocytes, synovial cells, and mononuclear cells by the proinflammatory cytokines TNF-alpha and IL-1, or by LPS. Large amounts of TSG-6 protein were found in synovial fluids of patients with rheumatoid arthritis. TSG-6 protein forms a stable complex with components of the serine protease inhibitor, inter-alpha-inhibitor (I alpha I). In this work, we show that TSG-6 potentiates the inhibitory effect of l alpha l on the protease activity of plasmin. The plasmin/plasminogen activator system is important in the protease network associated with inflammation. To test the hypothesis that through their cooperative inhibitory effect on plasmin TSG-6 and l alpha l can modulate the protease network and thus inhibit inflammation, we examined the effect of TSG-6 on experimentally induced inflammation. Human recombinant TSG-6 protein showed a potent anti-inflammatory activity in the murine air pouch model of carrageenan- or IL-1-induced acute inflammation. The inhibitory effect of locally administered TSG-6 on the IL-1-induced cellular infiltration was comparable with that of systemic dexamethasone treatment. Two mutant TSG-6 proteins with single amino acid substitutions close to the N terminus showed a complete or partial loss of anti-inflammatory activity. The anti-inflammatory effect of the TNF/IL-1-inducible TSG-6 protein, along with its ability to inhibit protease action through interaction with l alpha l, suggests that TSG-6 production during inflammation is part of a negative feedback loop operating through the protease network.
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PMID:TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo. 856 67

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


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