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)

Retinoic acid induces tissue-type plasminogen activator (t-PA) but not plasminogen activator inhibitor-1 (PAI-1) expression in cultured human umbilical vein endothelial cells (HUVEC). To further investigate the relation between the structure of the retinoids and their ability to induce t-PA synthesis in vitro, 11 analogues were studied in HUVEC culture. The retinoid analogues were classified into one of three groups according to their t-PA-inducing potential. Group 1 showed little induction (0.9- to 1.9-fold after 48 h) at concentrations between 10(-8) and 10(-6) M. Group 2, which includes all-trans-retinoic acid, induced t-PA threefold to fivefold at 10(-6) M but had little effect at 10(-8) M (less than threefold). Group 3, which comprises arotinoid acid (RO-13-7410) and RO-13-6307, induced t-PA antigen secretion fivefold at 10(-8) M. The retinoids of groups 2 and 3 had a terminal carboxyl group and alkyl substitution of the lipophylic head of the retinoid skeleton. The group 3 retinoids also contained an aromatic ring. The t-PA-inducing activity of these third-generation retinoids correlates to some extent with other activities, including regression of papilloma, keratinization in vivo, and clonal inhibition of tumor cell lines in vitro. Some of the retinoids caused a small but significant (up to 1.5-fold at 24 h) increase in PAI-1 antigen secretion. The group 3 retinoids appear to be sufficiently potent inducers of t-PA secretion to warrant further investigation in in vivo animal models.
 ...
PMID:Stimulation by retinoids of tissue-type plasminogen activator secretion in cultured human endothelial cells: relations of structure to effect. 138 May 92

The plasminogen activator activity of human synovial fibroblasts is raised by a monocyte-derived polypeptide, synovial activator and also by all-trans retinoic acid. The elevation of the synovial cell plasminogen activator activity by the two stimuli is potentiated both by agents which can raise cellular cyclic AMP levels, namely prostaglandin E2, cholera toxin and 3-isobutyl-1-methylxanthine, and also by exogenous 8-bromocyclic AMP. These findings suggest that there might be a substrate, which is phosphorylated by a cyclic AMP-dependent protein kinase and which is important in the modulation of the synovial cell plasminogen activator activity by the two stimuli. Prostanoids can be important in the stimulation of the synovial fibroblast plasminogen activator activity by mononuclear cell supernatants, since indomethacin can inhibit the increase in proteinase activity.
 ...
PMID:The stimulation of human synovial fibroblast plasminogen activator activity. Involvement of cyclic AMP and cyclooxygenase products. 242 80

The plasminogen activator produced by cultured human synovial fibroblasts was investigated both biochemically and immunologically. Stimulated either by all-trans-retinoic acid or by monocyte-conditioned medium, these fibroblasts elaborated a plasminogen activator with electrophoretic mobility similar to that of urokinase (Mr = 52 kilodaltons), and which also had immunologic cross-reactivity with urokinase. The plasminogen activator found in rheumatoid synovial fluids has been shown to be of the urokinase type. The findings reported here are consistent with the notion that synovial fibroblasts are a source of this proteinase.
 ...
PMID:Human synovial fibroblasts produce urokinase-type plasminogen activator. 309 41

Monocyte/macrophage polypeptides (monokines) alter the properties of synovial cells. This interaction could explain some of the properties of the inflamed synovium in rheumatic disease. Only recently has it been possible to test the action of purified monokines on the target synovial cells. We report here that recombinant human tumor necrosis factor alpha, tumor necrosis factor beta (lymphotoxin), interleukin-1 alpha, and interleukin-1 beta stimulate the hyaluronic acid (HA) levels of human synovial fibroblast-like cells. The effect of monokines was generally inhibited by indomethacin, suggesting the involvement of an endogenous cyclooxygenase product in the stimulation, and by the glucocorticoid, dexamethasone. In contrast, all-trans-retinoic acid stimulated synovial cell plasminogen activator activity but did not increase the HA levels. These findings could help to explain the raised HA levels found in the joint fluids and in the circulation of patients with rheumatic disease.
 ...
PMID:Stimulation of the hyaluronic acid levels of human synovial fibroblasts by recombinant human tumor necrosis factor alpha, tumor necrosis factor beta (lymphotoxin), interleukin-1 alpha, and interleukin-1 beta. 314 Aug 20

Cytokines capable of stimulating cartilage resorption have frequently been identified as 'interleukin-1 (IL-1)-like' peptides. In this study for the first time we have employed homogeneous recombinant IL-1 alpha and IL-1 beta in an all-human culture system to define the effects of IL-1 on articular cartilage and chondrocytes in culture. Recombinant IL-1 (10-100 U/ml) could stimulate cartilage resorption, although the maximum degree of tissue breakdown rarely reached the levels obtained when cartilage was treated with crude mononuclear-cell conditioned medium or all-trans retinoic acid (1 microM) over a similar time course. Levels of plasminogen activator (PA) activity, a neutral proteinase which may contribute to cartilage destruction in arthritis, increased markedly in the cartilage/chondrocyte culture supernatants and in the chondrocyte cell layers in response to the stimulation of cultures with recombinant IL-1 (1-100 U/ml). Elevated levels of PA activity were detectable after 4-8 h stimulation of the chondrocytes with IL-1 while characterization of the PA activities indicated that both types of PA activity were expressed, viz. urokinase-type PA (u-PA) and tissue-type PA (t-PA). Both IL-1 alpha and IL-1 beta could elicit these responses and their effects were comparable for a given dose. These studies show definitively that pure IL-1, free from contaminating cytokines, is capable of inducing human cartilage resorption and stimulating the expression of two types of PA activity by chondrocytes. In contrast to IL-1, retinoic acid increased the detectable levels of only u-PA in the chondrocyte cell layers. Chondrocyte u-PA may have an important role in cartilage degradative processes since it is one of the few neutral proteinases now known to be increased in activity in retinoid-stimulated cartilage.
 ...
PMID:Recombinant human interleukin-1 stimulates human articular cartilage to undergo resorption and human chondrocytes to produce both tissue- and urokinase-type plasminogen activator. 314 27

Treatment of simian virus 40-transformed 3T3 cells with 1 microM beta-all-trans-retinoic acid (RA) resulted in a 5- to 6-fold enhancement of plasminogen activator (PA) release. Intracellular PA levels rose to twice control levels. Confluent 3T3 cells were less responsive to RA. In 6 of 10 experiments, no increase in 3T3 cell PA levels was noted, although up to a 2.5-fold enhancement of PA elaboration has been observed in some experiments at a dose of 10 microM RA. Simultaneous treatments of 3T3 cells with 10 microM RA and 2.1 to 9.3 mM Ca2+, 5 to 40 ng phorbol myristate acetate per ml, or 150 to 600 ng Fraction I from lactalbumin hydrolysate (Fl) protein per ml indicated that RA potentiated the PA stimulatory activities of these agents. Extracellular PA levels of RA-treated cells increased by 4 to 10 times the amount of increase observed for Ca2+, PMA, or Fl alone. A potentiating activity of RA was also evident when quiescent 3T3 cells were pretreated with 10 microM RA and then stimulated to synthesize DNA with Ca2+, PMA, or Fl. For RA-pretreated cells, an increased percentage of nuclei was labeled with [3H]thymidine (24 hr) in response to doses of the three mitogens which were ineffective without RA pretreatment (2.4mM Ca2+, 5 ng PMA per ml, or 150 ng Fl protein per ml). Additional experiments have indicated that, like platelet extracts, Ra renders quiescent 3T3 cells competent to synthesize DNA in response to the progression factors of human plasma as defined by Pledger et al. (Proc. Natl. Acad. Sci. U. S. A., 74: 4481-4485, 1977). Pretreatment of quiescent 3T3 cells for 6 hr with 10 microM RA resulted in a greater than 4-fold increase in the percentage of cells which incorporated [3H]thymidine in response to a 36-hr treatment with 10% human plasma, as compared to cells treated with human plasma alone. Thus, under certain conditions, RA may have cell-activating properties, and caution should be exercised with regard to its suggested use as an antitumor agent.
 ...
PMID:Effects of retinoic acid on plasminogen activator and mitogenic responses of cultured mouse cells. 625 54

We studied the effects of two retinoids, naturally occurring all-trans-retinoic acid (retinoic acid) and the synthetic 4-hydroxyphenylretinamide (4-OH-PRT) on monolayer cultures of rabbit synovial fibroblasts and on explants of rabbit articular cartilage. Treatment of fibroblasts with phorbol myristate acetate (PMA; 10(-8) M) induced the synthesis and secretion of large amounts of collagenase: this was inhibited if the cells were treated with retinoic acid (10(-6) M) or dexamethasone (10(-7 M). Combined treatment with retinoic acid and the steroid prednisolone, at concentrations as low as 19(-10) M, gave an additive inhibition of collagenase production. Both retinoids inhibited collagenase production, but only 4-OH-PRT prevented the increase in prostaglandin E2 (PGE2) induced by PMA. Levels of plasminogen activator were also increased by treatment with PMA, and concomitant addition of either retinoid further enhanced this stimulation. Possible toxicity was assessed by measuring release of glycosaminoglycans (GAG) from explants of articular cartilage. Treatment with retinoic acid induced release of 80% of the total GAG, whereas treatment with 4-OH-PRT resulted in release of 40% of the total, a finding similar to that seen with untreated samples. 4-OH-PRT inhibited production of collagenase and PGE2 by rabbit synovial fibroblasts but was not toxic to articular cartilage.
 ...
PMID:Effects of all-trans-retinoic acid (retinoic acid) and 4-hydroxyphenylretinamide on synovial cells and articular cartilage. 627 10

Independent studies have previously shown that mononuclear cell supernatants stimulate the release of plasminogen activator and latent collagenase from synovial cell monolayer cultures. Simultaneous secretion of these enzymes could be an important pathway for tissue destruction under inflammatory conditions, since plasminogen activator can cause activation of latent collagenase in the presence of plasminogen. We investigated the kinetics of release of the two enzymes from synovial cells in response to the addition of mononuclear cell supernatants and retinoic acid. Synovial cells derived from osteoarthritic and rheumatoid arthritic patients responded similarly. Plasminogen activator is released within a few hours of stimulation, and secretion usually stops when the stimulus is removed. In contrast, significant amounts of collagenase are secreted only after an initial lag period of 1--2 days, and secretion is sustained long after removal of mononuclear cell supernatant. Another difference in regulation of the secretion of these two neutral proteinases is that the addition of all-trans retinoic acid to the same synovial cell culture elevates plasminogen activator secretion while suppressing that of latent collagenase. Differential regulation of these enzymes under conditions of chronic inflammation may allow for continual accumulation of latent enzyme(s) which are activated during short periods of plasminogen activator release.
 ...
PMID:Differential release of plasminogen activator and latent collagenase from mononuclear cell-stimulated synovial cells. 629 7

Synovial activator (SA) from peripheral blood mononuclear cells stimulates the plasminogen activator (PA) levels of human synovial fibroblasts. Using the sensitive technique of transcriptional inhibition followed by a prolonged translation period, data suggested that the first synthesis of mRNA needed for the increase in PA activity began within 40-60 min; this increase in protease activity was reversible on removal of SA from the cultures and also declined after about 3 days even if SA was not withdrawn. The RNA dependent events necessary for the synovial cell activation were to a large extent completed by about 4-8 h while those dependent on protein synthesis lasted for about 12 h. The effectiveness of suboptimal concentrations of SA could be potentiated by all-trans retinoic acid. A similar potentiation was effected by phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine and theophylline, by 8-bromo-cAMP, and by prostaglandins of the E and F series; these last observations suggest cyclic nucleotide involvement in the SA-mediated elevation of synovial fibroblast PA activity.
 ...
PMID:Synovial cell activation. Studies on the mechanism of action of synovial activator activity. 642 May 60

Nonrheumatoid human synovial fibroblasts in culture, while having low basal plasminogen activator levels, were stimulated to produce much more of this protease activity by low concentrations of a series of retinoids. The most potent retinoid tested, all-trans retinoic acid, was active over the range 10(-11)-10(-6)M. The increased plasminogen activator activity in the presence of 10(-6)M retinoic acid was first observed within 40 minutes under appropriate experimental conditions, required RNA and protein synthesis, and was reversible after short incubation periods. This stimulation was suppressed by low concentrations of antiinflammatory glucocorticoids such as dexamethasone.
 ...
PMID:Stimulation of the plasminogen activator activity of human synovial fibroblasts by retinoids. 720 Mar 64


1 2 3 4 Next >>