title: Non-steroidal anti-inflammatory drugs (NSAIDs) block the late, prostanoid-dependent/ceramide-independent component of ovarian IL-1 action: implications for the ovulatory process.
abstract: 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-1 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-1, PGS-2, IL-1beta, IL-1 receptor antagonist (IL-1RA) 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-1beta; however, it led to complete and highly significant dose-dependent blockade of the late (48 h) response to IL-1beta as assessed in terms of PGS-2 transcripts, proteins and activity. The addition of PGE2 to cells augmented the ability of IL-1beta to upregulate PGS-2 transcripts. Moreover, the addition of PGE2 to indomethacin-treated cells all but reversed the ability of indomethacin to suppress the IL-1beta effect at both the PGS-2 transcript and protein levels. The upregulation by IL-1 of IL-1beta, IL-1R and IL-1RA 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-1 action.
authors.affiliation: Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore 21201, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ando
authors.forename: S
authors.initials: S
authors.lastname: Kol
authors.forename: M
authors.initials: M
authors.lastname: Irahara
authors.forename: J
authors.initials: J
authors.lastname: Sirois
authors.forename: E Y
authors.initials: EY
authors.lastname: Adashi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002518:Ceramides / Q000378:metabolism / Q000502:physiology*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D010053:Ovary / Q000737:chemistry* / Q000166:cytology / Q000502:physiology; D010060:Ovulation / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D013110:Sphingosine / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002518:Ceramides; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011453:Prostaglandins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D011451:Prostaglandin-Endoperoxide Synthases; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine; D007213:Indomethacin