Glucocorticoid receptor-mediated post-ceramide inhibition of the interleukin-1 beta-dependent induction of ovarian prostaglandin endoperoxide synthase-2 in rats

Ovulation may constitute a cyclic, inflammatory-like process, wherein inter leukin (IL)-1 induction and increased biosynthesis of prostanoids may featu re prominently. In excess, glucocorticoids, potent anti-inflammatory agents , may exert an antiovulatory effect. This paper addresses the possibility t hat the antiovulatory action of glucocorticoids may be partly due to interf erence with ovarian prostanoid biosynthesis. Specifically, we examined the effect of treatment with dexamethasone, a synthetic glucocorticoid, on the IL-l-induced expression and activity of ovarian prostaglandin endoperoxide synthase (PCS)-2, the inducible variety of the rate-limiting enzyme in the prostaglandin cascade. Treatment of cultured whole ovarian dispersates from immature rats with dexamethasone for 48 h produced a significant decrease (98.9% inhibition) in the Ill-supported expression of PGS-2 transcripts. Co mparably marked inhibition was also noted for the corresponding immunoreact ive protein. The dexamethasone effect was not limited to the Il-1-mediated induction of PGS-2 transcripts, comparable suppression being noted for the IL-1-mediated up-regulation of ovarian transcripts corresponding to IL-1 be ta, the IL-1 receptor antagonist, and the type I IL-1 receptor. The order o f potency of the glucocorticoids studied was dexamethasone > prednisolone = cortisol. Dexamethasone proved equally effective in suppressing the induct ion of PGS-2 transcripts by congeners of the sphingomyelin-ceramide cycle ( e.g., C-2 ceramide, sphingomyelinase, and sphingosine), The dexamethasone e ffect proved glucocorticoid-specific, as synthetic agonists representative of the progestin (R-5020), androgen (R-1881), and estrogen (diethylstilbest rol) steroid series proved to be without effect. Cotreatment with RU-486 re sulted in reversal of the ability of dexamethasone to suppress PGS-2 activi ty or expression. Taken together, these observations suggest that dexametha sone is capable of glucocorticoid receptor-mediated/post-ceramide suppressi on of IL-1-supported ovarian PGS-2 transcript protein, and activity, These findings are compatible with the view that the chronic anovulatory state as sociated with adrenal hyperactivity or glucocorticoid excess may be due in part to inhibition of ovarian prostaglandin biosynthesis.