GLUCOCORTICOIDS SUPPRESS BASAL (BUT NOT INTERLEUKIN-1-SUPPORTED) OVARIAN PHOSPHOLIPASE A(2) ACTIVITY - EVIDENCE FOR GLUCOCORTICOID RECEPTOR-MEDIATED REGULATION

Ovulation may constitute a cyclic, inflammatory-like process, wherein the increased expression of interleukin (IL)-1 and the biosynthesis of prostaglandins may be established corollaries. In this communication we hypothesize that glucocorticoids, potent anti-inflammatory principl es, may exert an antiovulatory effect by interfering with ovarian IL-1 -driven prostaglandin biosynthesis. To lest this hypothesis, we examin ed the effect of treatment with dexamethasone on the activity of ovari an phospholipase A(2) (PLA(2)), the event-limiting enzyme in prostagla ndin biosynthesis, and on the gene expression pattern of secretory and cytosolic PLA(2) (sPLA(2) and cPLA(2), respectively). Whole ovarian d ispersates from immature rats were cultured under serum-free condition s for 48 h in the absence or presence of dexamethasone. Al the conclus ion of this culture period, PLA(2) activity was determined in cell son icates and conditioned media. Parallel probing for sPLA(2) and cPLA(2) transcripts was also undertaken using a solution hybridization/RNAse protection assay. Treatment of whole ovarian dispersates with dexameth asone produced a significant (P < 0.005) decrease in basal cellular an d extracellular PLA(2) activity to 27 and 40% of controls, respectivel y. A 5-fold decrease in the basal steady state levels of sPLA(2) (but not cPLA(2)) transcripts was also noted. Go-treatment with dexamethaso ne produced complete inhibition of IL-1-stimulated cPLA(2) transcripts but not of IL-1-supported cellular and extracellular PLA(2) activity or sPLA(2) transcripts. A glucocorticoid receptor antagonist (RU486), blocked the ability of dexamethasone to inhibit basal sPLA(2) transcri pts and extracellular PLA(2) activity. The inhibitory effect of dexame thasone proved glucocorticoid-specific in that aldosterone and 17 beta -estradiol were without effect. Taken together, these observations sug gest that dexamethasone is capable of inhibiting basal (but not IL-1-s upported) ovarian PLA(2) activity, a glucocorticoid receptor-mediated effect due, in part, to a decrease in sPLA(2) gene expression. Our fin dings further suggest that sPLA(2) and cPLA(2) are differentially regu lated and that they may well differ in their relative contribution to ovarian prostaglandin biosynthesis in general and to PLA(2) activity i n particular. To the extent that IL-1 plays a central role in the ovul atory process. these findings argue against the view that the chronic anovulatory state induced by glucocorticoid excess is due, if only in part, to suppression of ovarian IL-1-dependent PLA(2) activity. (C) 19 98 Published by Elsevier Science Ireland Ltd. All rights reserved.