DIFFERENTIAL REGULATION OF 11 BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 AND TYPE-2 BY NITRIC-OXIDE IN CULTURED HUMAN PLACENTAL TROPHOBLAST AND CHORIONIC CELL PREPARATION

Two types of 11 beta-hydroxysteroid dehydrogenase(11 beta-HSD) have be en identified in different tissues. Type 1 has both oxidase and reduct ase activities interconverting cortisol and cortisone, whereas type 2 has only oxidase activity converting cortisol to cortisone. It has bee n proposed that placental 11 beta-HSD controls the passage of maternal glucocorticoids to the fetal circulation. However, little is known ab out the regulation of 11 beta-HSD in the human placenta and fetal memb ranes. We cultured human term placental trophoblast and chorionic trop hoblast cells to examine effects of nitric oxide donors, sodium nitrop russide (SNP) and S-nitroso-N-acetyl penicillamine (SNAP), on the acti vity and messenger RNA (mRNA) expression of 11 beta-HSD. At 72 h of cu lture, placental trophoblast formed syncytial clumps that were cytoker atin positive and displayed mainly type 2 oxidase activity, although s ome type 1 reductase activity was detectable. Chorion preparations con tain greater than 90% trophoblast cells as demonstrated by immunostain ing for cytokeratin and less than 5% vimentin positive cells. Type 1 r eductase 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 a ctivity but not type 1 reductase activity either in placental or chori onic cells. An inhibitory effect on type 2 oxidase activity was reprod uced in part by 8-broma cGMP, blocked partially by the guanylate cycla se inhibitor LY83583 (1 mu M), but not by an ADP-ribosylation inhibito r N, N'-hexamethylene-bis-acetamide (HMBG) (10 mM). SNP also suppresse d the expression of type 2 mRNA in cultured placental trophoblast in a dose-dependent manner, and this effect was also blocked by LY83583. W e conclude that human placental trophoblast possesses predominantly 11 beta-HSD type 2 oxidase activity, whereas chorionic cells possess mai nly type 1 reductase activity under the culture conditions employed. N itric oxide specifically attenuated 11 beta-HSD type 2 oxidase activit y as well as its mRNA expression in the placental trophoblast. The eff ect was mediated at least partially through the cGMP pathway, although an alternative pathway other than ADP-ribosylation may exist.