Non-steroidal anti-inflammatory drugs (NSAIDs) block the late, prostanoid-dependent/ceramide-independent component of ovarian IL-1 action: implications for the ovulatory process

The therapeutic efficacy and antiovulatory properties of non-steroidal anti-inflammatory drugs (NSAIDs) is attributed to their ability to suppress prostaglandin endoperoxide synthase (PGS) activity. Given the likely role of interleukin (IL)-1 in the inflammatory (and probably the ovulatory) process, we set out to evaluate whether the antiovulatory property of NSAIDs is attributable, in part, to the inhibition of ovarian IL-I action. Whole ovarian dispersates from immature rats were cultured under serum-free conditions in the absence or presence of the indicated agents. At the conclusion of the culture period, total RNA was extracted and probed for transcripts corresponding to PGS-I, PGS-2, IL-1 beta, IL-1 receptor antagonist (IL-IRA) or type I IL-1 receptor (IL-1R) by a solution hybridization/ribonuclease protection assay. Treatment with indomethacin was without significant effect on the early (1 h) response to IL-1 beta; however, it led to complete and highly significant dose-dependent blockade of the late (48 h) response to IL-1 beta as assessed in terms of PGS-2 transcripts, proteins and activity. The addition of PGE, to cells augmented the ability of IL-1 beta to upregulate PGS-2 transcripts. Moreover, the addition of PGE, to indomethacin-treated cells all but reversed the ability of indomethacin to suppress the IL-1 beta effect at both the PGS-2 transcript and protein levels. The upregulation by IL-1 of IL-1 beta, IL-1R and IL-IRA transcripts was similarly inhibited by indomethacin. Taken together, these observations suggest that the anti-ovulatory property of NSAIDs may be due, in part, to blockade of the late, prostanoid-dependent component of ovarian IL-I action. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.