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Interleukin 1 Upregulates Ovarian Prostaglandin Endoperoxide Synthase-2 Expression: Evidence for Prostaglandin-Dependent/Ceramide-Independent Transcriptional Stimulation and for Message Stabilization¹

^a Divisions of Reproductive Endocrinology and ^b Human Genetics, Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, Maryland 21201 ^c Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Huntsman Cancer Institute, Salt Lake City, Utah 84112

We have recently documented a marked dependence of ovarian prostaglandin endoperoxide synthase (PGS)-2 transcripts, proteins, and activity on interleukin (IL) 1, a putative intermediary in the ovulatory cascade. The purpose of the present study was to characterize the cellular and molecular mechanisms underlying the ability of IL-1ß to upregulate the steady-state levels of ovarian transcripts corresponding to PGS-2. Results of studies designed to enrich or deplete nitric oxide strongly suggest that the stimulatory effect of IL-1ß on ovarian PGS-2 expression is independent of nitric oxide. Utilization of a series of agents designed to simulate or enhance transduction via the sphingomyelin ceramide cycle suggests that the long-term stimulatory effect of IL-1ß on ovarian PGS-2 gene expression is independent of ceramide. In contrast, inhibition of prostaglandin biosynthesis with a series of distinct inhibitors suggests that the ability of IL-1ß to upregulate ovarian PGS-2 transcripts is due, if only in part, to the generation of endogenous prostaglandin estradiol-17ß (E₂). Inhibition of protein biosynthesis suggested that the IL-1ß-induced PGS-2 gene expression required de novo protein biosynthesis. Our findings revealed substantial IL-1ß-mediated stabilization of PGS-2 transcripts, as assessed by a threefold increase in the half-life of the message. We have also observed the ability of IL-1ß to upregulate the transcription of PGS-2 promoter constructs subjected to transient transfection into whole-ovarian dispersates (twofold increase as assessed by activation of the luciferase reporter gene). Taken together, these findings suggest that the stimulatory effect of IL-1ß on PGS-2 expression is 1) independent of nitric oxide as well as ceramide, 2) dependent on prostaglandin E₂, 3) contingent on de novo protein biosynthesis, and 4) accounted for by both increased transcription and message stabilization. These observations provide indirect support for the hypothesis that IL-1ß, acting in part through PGS-2 (an obligatory ovulatory principal), may constitute a key intermediary in the ovulatory cascade.

First decision: 22 November 2000.

¹ Supported in part by NIH Research Grant HD-30288 (to E.Y.A.).

² Correspondence: Eli Y. Adashi, Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Huntsman Cancer Institute, 2000 Circle of Hope, Room 5221, Salt Lake City, UT 84112. FAX: 801 585 9256; eadashi{at}hsc.utah.edu

³ Current address: Department of Obstetrics and Gynecology, Kyorin University School of Medicine, Tokyo 181, Japan.

⁴ Current address: Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kanagawa 216, Japan.

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