Recent studies have established the existence of a complete intraovarian Interleukin-1 (IL-1) system, replete with ligands, receptors, and a receptor antagonist. This new proposal seeks to test the hypothesis that intraovarian IL-1 may play an intermediary role in the ovulatory process. More specifically, it is hypothesized that intraovarian IL-1beta (of theca-interstitial or resident macrophage origin) may constitute a mediator of gonadotropins in the induction of ovulation, an effector capable of coordinating and amplifying key components of the ovulatory cascade. Support for this hypothesis can be derived from 1) the demonstration of hCG-dependent preovulatory induction of IL-1beta transcripts in the murine as well as human ovary, 2) the observation of the in vitro ability of IL-1beta to activate several established components of the preovulatory cascade [e.g. collagenase generation, proteoglycan/hyaluronic acid production, and prostaglandin biosynthesis], and 3) the documentation of the in vitro capacity of IL-1beta to induce ovulation, promote oocyte maturation, as well as allow fertilization, and subsequent early embryonic development. Consequently, the midcycle gonadotropin surge-induced intraovarian IL-1beta may constitute the centerpiece of a regulatory cascade concerned with ovulation. Such a notion is in keeping with the presumption that ovulation may constitute an inflammatory-like process and the recognition that IL-1 is an established mediator of inflammation. To test the above hypothesis, to gain further insight into the workings of the intraovarian IL-1 system, and to provide irrefutable in vivo evidence for a role of IL-1 in normal ovarian physiology, a series of complementary in vivo and in vitro experiments are proposed. To directly assess the potential relevance of IL-1 to the ovulatory process, the in vivo ability of exogenous IL-1 to bring about ovulation (resulting in fertilization and early embryonic development) in PMSG-primed immature rats will be assessed and characterized. Moreover, a specific recombinant IL-1 receptor antagonist will be evaluated for its in vivo ability to block IL-1 or gonadotropin- induced ovulation (Aim I). significant attention will also be paid to the identification of the ovarian subtypes (I & II) of IL-1 receptors, their cellular localization, periovulatory expression, and hormonal regulation. In this connection, measurements of the corresponding gene transcripts as well as of the presumptive protein products will be carried out (Aim II). Similar studies are proposed for the IL-1 receptor antagonist in recognition of its role as a determinant of net intraovarian IL-1 activity (Aim III). Lastly, the cellular mechanism(s) by which IL-1 stimulates ovarian prostaglandin biosynthesis will be addressed (Aim IV). The long-term goal of this investigation is to develop an improved understanding of the molecular mechanism(s) by which IL-1 may participate in the ovulatory process. Such insight may result in the elucidation of some of the molecular events underlying the ovulatory process, in the delineation of the reproductive side effects of systemic anti-IL-1 therapy (currently in early phase clinical trials), and in potentially improved strategies for the promotion of fertility of its control.
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