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Differential Regulation of 11 ß-Hydroxysteroid Dehydrogenase Type 1 and 2 by Nitric Oxide in Cultured Human Placental Trophoblast and Chorionic Cell Preparation¹

Medical Research Council Group in Fetal and Neonatal Health and Development (K.S., J.R.G.C.), Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and Departments of Obstetrics and Gynaecology and Physiology, University of Western Ontario (K.Y.), Ontario, Canada

Address all correspondence and requests for reprints to: Kang Sun, Department of Physiology, University of Toronto, Faculty of Medicine, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada. E-mail: kang.sun{at}utoronto.ca

Two types of 11 ß-hydroxysteroid dehydrogenase (11 ß-HSD) have been identified in different tissues. Type 1 has both oxidase and reductase activities interconverting cortisol and cortisone, whereas type 2 has only oxidase activity converting cortisol to cortisone. It has been proposed that placental 11 ß-HSD controls the passage of maternal glucocorticoids to the fetal circulation. However, little is known about the regulation of 11 ß-HSD in the human placenta and fetal membranes. We cultured human term placental trophoblast and chorionic trophoblast cells to examine effects of nitric oxide donors, sodium nitroprusside (SNP) and S-nitroso-N-acetyl penicillamine (SNAP), on the activity and messenger RNA (mRNA) expression of 11 ß-HSD. At 72 h of culture, placental trophoblast formed syncytial clumps that were cytokeratin positive and displayed mainly type 2 oxidase activity, although some type 1 reductase activity was detectable. Chorion preparations contain greater than 90% trophoblast cells as demonstrated by immunostaining for cytokeratin and less than 5% vimentin positive cells. Type 1 reductase activity predominated in the chorionic trophoblast cells with barely detectable type 1 or type 2 oxidase activity. Both SNP (1–400 µM) and SNAP (1 mM) inhibited placental 11 ß-HSD type 2 oxidase activity but not type 1 reductase activity either in placental or chorionic cells. An inhibitory effect on type 2 oxidase activity was reproduced in part by 8-bromo cGMP, blocked partially by the guanylate cyclase inhibitor LY83583 (1 µM), but not by an ADP-ribosylation inhibitor N, N'-hexamethylene-bis-acetamide (HMBG) (10 mM). SNP also suppressed the expression of type 2 mRNA in cultured placental trophoblast in a dose-dependent manner, and this effect was also blocked by LY83583. We conclude that human placental trophoblast possesses predominantly 11 ß-HSD type 2 oxidase activity, whereas chorionic cells possess mainly type 1 reductase activity under the culture conditions employed. Nitric oxide specifically attenuated 11 ß-HSD type 2 oxidase activity as well as its mRNA expression in the placental trophoblast. The effect was mediated at least partially through the cGMP pathway, although an alternative pathway other than ADP-ribosylation may exist.

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