Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differential expression of PAI-1 in connective tissues has been associated etiologically with some forms of arthritis. Our objective was to delineate the mechanisms by which PGE2 and IL-1 beta, inflammatory mediators commonly found at sites of inflammation, regulate the expression and synthesis of PAI-1 in human synoviocytes. PGE2 (and PGE1) inhibited PAI-1 mRNA expression and secretion in a dose-dependent manner with an IC50 (for antigen secretion) of 4.6 x 10(-10) M and 8.7 x 10(-10) M, respectively. Cyclic AMP agonists forskolin, Sp-cAMP, and IBMX mimic the effects of the PGEs. rhIL-1 beta stimulated the secretion of PAI-1 in a dose-dependent fashion under basal culture conditions; the effect was reversed by actinomycin D and the protein kinase inhibitors H7 and staurosporine but not KT-5720. PMA, an activator of protein kinase C, transiently increased (maximum 3 h) the expression of PAI-1 mRNA by approximately 10-fold, especially the 3.2 kb species. However, there was no significant increase in PAI-1 antigen secreted into the culture medium after PMA (100-300 nM) treatment. The half-life (t1/2) of PAI-1 mRNA, both the 3.2 and 2.2 transcripts was about 9.6 h (mean n = 3) and PGE2 has no affect on the stability of both messages. PGE2 reduced the rate of PAI-1 gene transcription as judged by run-off assays. The NSAID naproxen (30 micrograms/ml) induced the expression of PAI-1 mRNA over basal levels and super-induced the inhibitor's expression above rhIL-1 beta stimulated levels. Our results suggest that PGE2 suppresses PAI-1 expression and synthesis by activation of the cAMP/PKA system and inhibition of the rate of gene transcription. Data concerning the activation of PKC suggest that the expression, synthesis and release of the PAI-1 may be differentially regulated in normal human synoviocytes.
Mol Cell Endocrinol 1994 Jul
PMID:Transcriptional regulation of plasminogen activator inhibitor-1 expression in human synovial fibroblasts by prostaglandin E2: mediation by protein kinase A and role of interleukin-1. 752 83

Protein phosphatases regulate the activity of signal transduction mechanisms by dephosphorylating activated components. By utilizing selective inhibitors of these phosphatases, we investigated their role in regulating cAMP accumulation in the UMR 106 osteoblast-like tumor cell line. PTHrP, PTH and PGE2 stimulated cAMP accumulation up to 100-fold. Calyculin A, a potent inhibitor of protein phosphatase type 1 (PP1) and type 2A (PP2A), did not affect basal levels of cAMP, but concentrations of 10(-11) M to 10(-8) M increased PTHrP-, PTH-, and PGE2-stimulated cAMP accumulation up to 1.7-fold, and this increase was concentration-dependent. Similar results were obtained with tautomycin, another potent inhibitor of PP1 and PP2A. In contrast, okadaic acid, a potent inhibitor of PP2A which inhibited PP1 less potently, did not enhance PTHrP-, PTH-, or PGE2-stimulated cAMP accumulation. The effect of calyculin A on agonist-stimulated cAMP accumulation persisted in cells treated with isobutyl methylxanthine, a phosphodiesterase inhibitor. When the effect of calyculin A was compared with that of 4 beta-phorbol 12-myristate 13-acetate (PMA), it was found that while PMA enhanced both the receptor and forskolin-stimulated cAMP accumulation, calyculin A had no effect on the forskolin-stimulated cAMP accumulation. The effect of calyculin A on PTHrP- and PTH-stimulated cAMP accumulation persisted in cells treated with PMA. These results suggest that protein phosphatases play an important role in agonist-stimulated cAMP accumulation in osteoblast-like cells, and that PP1 but not PP2A may be the major phosphatase involved. In contrast to activation by protein kinase C, the site of action for the phosphatase appears to be predominantly at a step prior to the activation of adenylyl cyclase in the cAMP signal transduction pathway.
Mol Cell Endocrinol 1995 Apr 28
PMID:Inhibition of serine/threonine protein phosphatases enhances agonist-stimulated cAMP accumulation in UMR 106 osteoblast-like cells. 754 25

We measured prostaglandins (PGs) in human pleural effusions of 43 patients with various diseases using microcolumn high performance liquid chromatography with a He/Cd laser induced fluorescence detection system. PGD2 was not detected in the transdate effusions. In contrast, PGD2 was detected in pleural exudates (malignant effusions: 0.22 +/- 0.07 nmol/ml, tuberculous effusions: 0.28 +/- 0.08 nmol/ml). PGE2 and 6-keto-PGF1 alpha concentrations in malignant effusions (1.62 +/- 0.17 nmol/ml, 14.40 +/- 1.33 nmol/ml, respectively) were significantly increased compared with tuberculous effusions (0.98 +/- 0.13 nmol/ml, 10.36 +/- 0.92 nmol/ml) and transdates (0.60 +/- 0.06 nmol/ml, 6.91 +/- 0.61 nmol/ml). On the contrary, there was no significant difference in PGF2 alpha concentrations between malignant effusions and tuberculous effusions. From these results, not only PGE2 but also PGD2 and PGI2 might be implicated in the pleural fluid accumulation.
Biochem Mol Biol Int 1995 Jul
PMID:Laser high performance liquid chromatography determination of prostaglandins in pleural effusions. 754 50

We studied the direct effects of PGE2, often produced at high levels by mammary tumours, on three human breast cancer cell lines diversely advanced in malignancy regarding differentiation and tumorigenicity in nude mice. We evaluated PGE2 effect on cell growth, PGE2 receptor level and functionality. Our results show that PGE2 induces cAMP accumulation and inhibits the growth of the most differentiated breast cancer cells. We also demonstrate that loss and probably dysfunction of PGE2 receptors is related to an advanced tumorigenic phenotype of the cells. Thus, it seems that during progression of breast cancer, the cell growth escapes from control by PGE2. Nevertheless, it is possible to control the growth of advanced breast cancer cells in vitro by direct induction of intracellular cAMP accumulation.
Mol Cell Endocrinol 1995 Jun
PMID:Alteration of prostaglandin E receptors in advanced breast tumour cell lines. 755 85

The effect of individual unsaturated fatty acids on the release of tumour necrosis factor (TNF) and interleukin 6 (IL6) was investigated in thioglycollate-induced rat peritoneal macrophages. The intracellular mechanisms associated with the changes of cytokine production in response to fatty acids were also studied. Incubation of macrophages with 100 microM docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) increased TNF (21% and 15% respectively) and IL6 (69% and 40% respectively) production. Linoleic acid (LA) diminished TNF production by 16%. At 100 microM oleic acid (OA), LA and EPA concentration an increase in macrophage adenylate cyclase activity (110%, 72% and 39% respectively) and a decrease (14%) in the presence of DHA was observed. PGE2 production in the presence of 100 microM DHA was reduced by 36%, whereas in the presence of 100 microM LA an increase (75%) was observed. Phospholipase A2 (PLA2) activity was also found to be modified in the presence of EPA and DHA at 50 microM (20% and 60% respectively) and 100 microM (34% and 62% respectively) concentrations. The activities of both protein kinase A (PKA) and protein kinase C (PKC) were effected by the different fatty acids. At 50 microM all fatty acids suppressed PKA activity except OA which enhanced PKA activity by 14%. At 100 microM fatty acid concentration, EPA suppressed PKA activity by 40%. PKC activity was enhanced by LA and OA, by 18% and 21% respectively. However, at 100 microM EPA and DHA, PKC activity was suppressed by 37% and 17% respectively, whereas PKC activity was enhanced by 146% in the presence of 100 microM LA. These results show for the first time that unsaturated fatty acids have an effect on macrophage PLA2 activity and that PGE2 may be a potent modulator of IL6 production. From these studies it is tempting to speculate that macrophage TNF and IL6 release may, in part, occur via a PKC and PKA independent pathway and that PLA2 activity and PGE2 concentration are inversely related to production of TNF and IL6.
Mol Cell Biochem 1995 Feb 23
PMID:Influence of unsaturated fatty acids on the production of tumour necrosis factor and interleukin-6 by rat peritoneal macrophages. 759 52

Dopamine-induced saliva from ticks fed [3H]arachidonic acid contained the radiolabelled prostaglandins E2, F2 alpha, D2, and B2, the latter probably derived from PGE2 owing to the alkalinity of tick saliva. Prostaglandin synthetase (PGS) activity in the salivary gland homogenate from the lone star tick, Amblyomma americanum, could not be detected by standard radiometric methodologies successfully employed for tissues from many animal species, including numerous arthropods. Modifications to the assay conditions had no effect. The presence of a PGS-inhibitor in the salivary glands was ruled out. It is postulated that the PGS in A. americanum salivary glands may be considerably different from that found in other animals, including vertebrate hosts.
Insect Biochem Mol Biol 1995 Jun
PMID:Biosynthesis of salivary prostaglandins in the lone star tick, Amblyomma americanum. 762 5

We describe eicosanoid biosynthesis by microsomal-enriched preparations of hemocytes from larvae of the tobacco hornworm Manduca sexta. Four major prostaglandins, PGA2, PGE2, PGD2, and PGF2 alpha, and a lipoxygenase product that co-chromatographed with 15-hydroxyeicosatetraenoic acid (HETE) were synthesized under most conditions. The HETE's fraction was the predominant product. Eicosanoid biosynthesis was sensitive to experimental conditions, including incubation time, temperature, and protein concentration. Optimal biosynthesis was observed with 1.5 mg of microsomal-enriched protein, incubated at 30 degrees C for 2 min. The hemocyte preparation is sensitive to low dosages of naproxin and esculetin. As in mammals, most lipoxygenase activity (87%) was localized in the cytosolic fraction of hemocytes. Unlike mammals, in which PGH synthase is associated with intracellular membranes, the hemocytic activity was detected in microsomal (59%), cytosolic (35%) and mitochondrial fractions (5%).
Insect Biochem Mol Biol 1995 Jun
PMID:Eicosanoid biosynthesis by hemocytes from the tobacco hornworm, Manduca sexta. 762 6

The CD44 adhesion receptor is a hyaluronan-binding cell surface glycoprotein whose major isoform is a 95 kDa molecule with a wide tissue distribution. We have characterized two MAbs, W4/86 and RPN3/24, by immunochemistry, flow cytometry and fluorescence staining and demonstrated that they recognize the rabbit CD44 molecule. The results show that CD44 in the rabbit has a similar molecular size and cell distribution to human CD44. These antibodies have demonstrated for the first time, the presence of CD44 on synoviocytes. Preincubation of the rabbit synovial cell line HIG-82 with W4/86 inhibited its synthesis of PGE2 in response to autocrine synovial cytokines. These results indicate that the CD44 molecule may help to modulate synoviocyte metabolism.
Mol Immunol 1993 Oct
PMID:Characterization of monoclonal antibodies against rabbit CD44: evidence of a role for CD44 in modulating synoviocyte metabolism. 769 87

Infections, trauma and inflammatory processes induce a host response with increases in a large group of structurally and functionally diverse plasma proteins. Parental administration of foreign proteins also induce an increase in plasma fibrinogen. Interleukin-6 (IL-6) is a monocyte-derived mediator and has regulatory effects on acute phase protein genes which result in the induction of fibrinogen synthesis in primary hepatocytes, while the addition of interleukin-1 (IL-1) exerts a negative modulating influence on the IL-6-stimulated fibrinogen. In order to understand the mechanisms by which IL-1 inhibits IL-6-stimulated fibrinogen transcription and translation, and since IL-1 is believed to act through PGE2 stimulation, we have studied the influence of PGE2 in IL-6 or IL-1, alone and in combination, on Fg mRNA expression (by Northern blot analysis) and the influence of PGE2, indomethacin, and arachidonic acid on Fg secretion. Moreover, since human recombinant interleukin-1 receptor antagonist (hrIL-1ra) is a strong inhibitor of IL-1 induced IL-1 transcription and translation and has an inhibitory effect on PGE2, we have studied the effects of IL-1ra on the down-regulation of IL-6 stimulated fibrinogen by IL-1, using an Fg ELISA method.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1995 Jan 26
PMID:The down-regulation of IL-6-stimulated fibrinogen steady state mRNA and protein levels by human recombinant IL-1 is not PGE2-dependent: effects of IL-1 receptor antagonist (IL-1RA). 777 69

Prostaglandins E1 (PGE1) and E2 (PGE2), the general local modulators or "local" hormones, were able to inhibit the progesterone-induced maturation of Xenopus oocytes in vitro, but could not induce maturation by themselves. This inhibition was observed on the sensitivity of the maturation process of the oocyte responses to progesterone, but not on the maximum response or responsiveness. The decreased sensitivity of oocytes to progesterone by prostaglandin E1 or E2 was evident in both the increased concentration of progesterone and the prolonged time required for the maturation of 50% of the oocyte. PGE1 and PGE2 did not appear to affect either the basal level or the progesterone-reduced cAMP level of oocytes. Microinjection of PGE1 or PGE2 into the oocytes had no effect on progesterone-induced oocyte maturation, suggesting that other cell surface-mediated signaling events might be responsible for this modulatory effect of the progstaglandins.
Cell Mol Biol Res 1994
PMID:Modulation of progesterone-induced Xenopus oocyte maturation by prostaglandins E1 and E2. 780 27


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