Differential regulation of 11 beta-hydroxysteroid dehydrogenase type 1 and 2 by nitric oxide in cultured human placental trophoblast and chorionic cell preparation

Two types of 11 beta-hydroxysteroid dehydrogenase(11 beta-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 beta-HSD controls the passage of maternal glucocorticoids to the fetal circulation. However, little is known about the regulation of 11 beta-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 beta-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 I or type 2 oxidase activity. Both SNP (1-400 mu M) and SNAP (1 mM) inhibited placental 11 beta-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-broma cGMP, blocked partially by the guanylate cyclase inhibitor LY83583 (1 mu M), 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 beta-HSD type 2 oxidase activity, whereas chorionic cells possess mainly type 1 reductase activity under the culture conditions employed. Nitric oxide specifically attenuated 11 beta-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.