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Mechanism of Cortisol/Progesterone Antagonism in the Regulation of 15-Hydroxyprostaglandin Dehydrogenase Activity and Messenger Ribonucleic Acid Levels in Human Chorion and Placental Trophoblast Cells at Term

Canadian Institutes for Health Research Group in Fetal and Neonatal Health and Development, Departments of Physiology and Obstetrics and Gynecology, University of Toronto (F.A.P., J.R.G.C.), Toronto, Ontario, Canada M5S 1A8; and Prince Henry’s Institute for Medical Research (J.W.F.), Clayton, Victoria, 8008 Australia

Address all correspondence and requests for reprints to: Dr. Falguni A. Patel, Department of Physiology, Faculty of Medicine, University of Toronto, 1 Kings College Circle, Medical Sciences Building, Room 3344, Toronto, Ontario, Canada M5S 1A8. E-mail: fal.patel{at}utoronto.ca.

Prostaglandin dehydrogenase (PGDH) metabolizes prostaglandins (PGs) to render them inactive. We reported previously that cortisol (F) decreases and progesterone (P₄) maintains PGDH activity/expression in human chorion and placenta. Furthermore, we have shown that F and P₄ compete for regulation of PGDH. We hypothesized that P₄ maintains PGDH activity through interaction with the glucocorticoid receptor (GR) and that elevations in F compete with P₄ at the GR, resulting in a decrease in PGDH at term. By immunohistochemistry and Western blotting analysis, we localized immunoreactive GR and progesterone receptor (PR) to chorion and placental trophoblast cells. We treated chorion and placental trophoblast cells in culture with F, dexamethasone (DEX), ß-methasone, P₄, trilostane (a 3ß-hydroxysteroid dehydrogenase inhibitor), medroxyprogesterone acetate (MPA), and/or 21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione (21OH-6OP; a GR antagonist). By RIA and Northern blotting analysis, all glucocorticoids (GCs) decreased PGDH activity/expression. Coincubation with 21OH-6OP reversed GC inhibition of PGDH; MPA, but not P₄, treatment stimulated PGDH activity. Trilostane inhibited PGDH activity, and coincubation with P₄ or MPA reversed trilostane inhibition of PGDH. Treatment with trilostane, P₄, 21OH-6OP, or MPA plus 21OH-6OP reversed P₄ and MPA up-regulation of PGDH activity. Our findings suggest that F inhibition and P₄ stimulation of PGDH may be mediated by PR, but also via the GR, in chorion and placenta.

This work was supported by the Canadian Institutes for Health Research.

Abbreviations: Ab, Antibody; AP-1, activating protein-1; CBP, CREB binding protein; CRE, cAMP response element; CREB, cAMP response element-binding protein; DEX, dexamethasone; F, cortisol; GC, glucocorticoid; GR, glucocorticoid receptor; GRE, glucocorticoid response element; HSD, hydroxysteroid dehydrogenase; IR-, immunoreactive; MPA, medroxyprogesterone acetate; NF-B, nuclear factor-B; 21OH-6OP, 21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione; P₄, progesterone; PBS-T, PBS-Tris; PG, prostaglandin; PGDH, prostaglandin dehydrogenase; PGFM, 13,14-dihydro-15-keto PGF₂; PR, progesterone receptor; ROD, relative OD.

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