Glucocorticoids suppress basal (but not interleukin-1-supported) ovarian phospholipase A 2 activity : : Evidence for glucocorticoid receptor-mediated regulation

Abstract

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 principles, may exert an antiovulatory effect by interfering with ovarian IL-1-driven prostaglandin biosynthesis. To test this hypothesis, we examined the effect of treatment with dexamethasone on the activity of ovarian phospholipase A 2 (PLA 2), the event-limiting enzyme in prostaglandin biosynthesis, and on the gene expression pattern of secretory and cytosolic PLA 2 (sPLA 2 and cPLA 2, respectively). Whole ovarian dispersates from immature rats were cultured under serum-free conditions for 48 h in the absence or presence of dexamethasone. At the conclusion of this culture period, PLA 2 activity was determined in cell sonicates 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 dexamethasone produced a significant ( P<0.005) decrease in basal cellular and extracellular PLA 2 activity to 27 and 40% of controls, respectively. A 5-fold decrease in the basal steady state levels of sPLA 2 (but not cPLA 2) transcripts was also noted. Co-treatment with dexamethasone 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 transcripts and extracellular PLA 2 activity. The inhibitory effect of dexamethasone proved glucocorticoid-specific in that aldosterone and 17 β-estradiol were without effect. Taken together, these observations suggest that dexamethasone is capable of inhibiting basal (but not IL-1-supported) ovarian PLA 2 activity, a glucocorticoid receptor-mediated effect due, in part, to a decrease in sPLA 2 gene expression. Our findings further suggest that sPLA 2 and cPLA 2 are differentially regulated and that they may well differ in their relative contribution to ovarian prostaglandin biosynthesis in general and to PLA 2 activity in particular. To the extent that IL-1 plays a central role in the ovulatory 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.