INTERLEUKIN-1: AN INTERMEDIARY IN OVULATION

最近的研究已经证实存在一个完整的卵巢内 白细胞介素-1（IL-1）系统，充满配体、受体和一种 受体拮抗剂 这一新提议试图检验以下假设： 卵巢内IL-1可能在排卵过程中起中介作用。 更具体地说，假设卵巢内IL-1 β（ 膜间质或驻留巨噬细胞来源）可构成 促性腺激素诱导排卵的介质，效应物 能够协调和放大排卵的关键成分， 级联。 支持这一假设可以从1） 证明hCG依赖性排卵前诱导IL-1 β 在小鼠以及人卵巢中的转录物，2）观察 IL-1 β体外激活几种已建立 排卵前级联的组分[例如胶原酶的产生， 蛋白聚糖/透明质酸生产和前列腺素生物合成]， 和3）IL-1 β体外诱导细胞凋亡的能力的证明。 排卵，促进卵母细胞成熟，以及允许受精， 早期胚胎发育。 因此，中期 促性腺激素激增诱导的卵巢内IL-1 β可能构成 这是与排卵有关的一系列调节的核心。 这样的 这一概念与排卵可能构成 炎症样过程和认识到IL-1是 炎症介质。 为了验证上述假设， 进一步深入了解卵巢内IL-1系统的运作， 并为IL-1在正常人中的作用提供了无可辩驳的体内证据， 卵巢生理学，一系列互补的体内和体外 实验提出。 直接评估潜在的相关性 IL-1对排卵过程的影响，外源性IL-1在体内对排卵过程的影响， 引起排卵（导致受精和早期胚胎 将评估PMSG致敏的未成熟大鼠中的发育）， 表征了 此外，特异性重组IL-1受体拮抗剂 将评估其体内阻断IL-1或促性腺激素的能力， 诱导排卵（Aim I）。 还将特别注意 IL-1受体的卵巢亚型（I和II）的鉴定， 它们的细胞定位、排卵期表达和激素水平 调控 在这方面，测量相应的基因 转录本以及假定的蛋白质产物将被 目标（二）。 对IL-1受体也进行了类似的研究 拮抗剂，以确认其作为净的决定因素的作用 卵巢内IL-1活性（Aim III）。 最后，细胞机制（S） IL-1刺激卵巢前列腺素生物合成的机制， 目标四（Aim IV） 这项调查的长期目标是 提高对分子机制的理解， IL-1可能参与排卵过程。 这种洞察力可能导致 在阐明一些分子事件的基础上， 排卵过程，在描绘生殖副作用 全身性抗IL-1治疗（目前处于早期临床试验阶段）， 以及可能改进的提高生育率战略， 它的控制。

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.