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Role for Prostaglandins in the Regulation of Type 1 11ß-Hydroxysteroid Dehydrogenase in Human Granulosa-Lutein Cells

Department of Biochemistry and Molecular Biology (K.C.J., C.C., A.E.M.), Royal Free and University College Medical School, University College London, London WC1E 6BT, United Kingdom; Department of Veterinary Basic Science (K.C.J., C.C., D.R.E.A.), Royal Veterinary College, London NW1 0TU, United Kingdom; and Centre for Developmental and Endocrine Signalling (A.E.M.), Academic Section of Obstetrics & Gynaecology, Division of Clinical Developmental Sciences, St. George’s, University of London, London SW17 0RE, United Kingdom

Address all correspondence and requests for reprints to: Dr. Kim C. Jonas, Department of Veterinary Basic Science, Royal Veterinary College, Royal College Street, London NW1 0TU, United Kingdom. E-mail: kjonas{at}rvc.ac.uk.

11ß-Hydroxysteroid dehydrogenase (11ßHSD) enzymes regulate glucocorticoid availability in target tissues. 11ßHSD1 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 11ßHSD1 activities and expression in hGL cells. The consequences for 11ßHSD1 of increasing exposure of hGL cells to PGs, either by treatment with exogenous PGs or by challenging cells with IL-1ß, 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 11ßHSD1 were suppressed by up to 64 ± 6% (P < 0.05). Over 4 and 24 h, neither MA nor NS-398 affected the expression of 11ßHSD1 protein, suggesting enzyme regulation by PGs at the posttranslational level. When cells were cotreated for 4 h with PGHS inhibitors plus 30 nM PGD₂, PGF₂, or PGE₂, each PG overcame the suppression of cortisol oxidation by indomethacin or MA. Treatment of hGL cells with IL-1ß increased the concentrations of both PGE₂ and PGF₂, accompanied by a 70 ± 25% increase in net cortisol oxidation. All three responses to IL-1ß were abolished when cells were cotreated with MA. These findings suggest a role for PGs in the posttranslational regulation of 11ßHSD1 activities in hGL cells.

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