Role for prostaglandins in the regulation of type 1 11beta-hydroxysteroid dehydrogenase in human granulosa-lutein cells.
11beta-hydroxysteroid dehydrogenase (11betaHSD) enzymes regulate glucocorticoid availability in target tissues. 11betaHSD1 is the predominant isoenzyme expressed and active in human granulosa-lutein (hGL) cells. This study investigated the effects of pharmacological inhibitors of prostaglandin (PG) synthesis on 11betaHSD1 activities and expression in hGL cells. The consequences for 11betaHSD1 of increasing exposure of hGL cells to PGs, either by treatment with exogenous PGs or by challenging cells with IL-1beta, were also assessed. Suppression of basal PG synthesis using four different inhibitors of PG H synthase enzymes [indomethacin, niflumic acid, meclofenamic acid (MA) and N-(2-cyclohexyloxy-4-nitorophenyl) methane sulfonamide (NS-398)] each resulted in significant decreases in both cortisol oxidation and cortisone reduction. Both activities of 11betaHSD1 were suppressed by up to 64+/-6% (P<0.05). Over 4 and 24 h, neither MA nor NS-398 affected the expression of 11betaHSD1 protein, suggesting enzyme regulation by PGs at the posttranslational level. When cells were cotreated for 4 h with PGHS inhibitors plus 30 nm PGD2, PGF2alpha, or PGE2, each PG overcame the suppression of cortisol oxidation by indomethacin or MA. Treatment of hGL cells with IL-1beta increased the concentrations of both PGE2 and PGF2alpha, accompanied by a 70+/-25% increase in net cortisol oxidation. All three responses to IL-1beta were abolished when cells were cotreated with MA. These findings suggest a role for PGs in the posttranslational regulation of 11betaHSD1 activities in hGL cells.
Jonas
Kim C
KC
Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College London, UK. kjonas@rvc.ac.uk
Chandras
Christina
C
Abayasekara
D Robert E
DR
Michael
Anthony E
AE
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008184:Luteal Cells / Q000201:enzymology*; D008469:Meclofenamic Acid / Q000494:pharmacology; D008954:Models, Biological; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D053583:Interleukin-1beta; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D008469:Meclofenamic Acid; D042842:11-beta-Hydroxysteroid Dehydrogenases; D011451:Prostaglandin-Endoperoxide Synthases