INTERLEUKIN-1: AN INTERMEDIARY IN OVULATION

最近的研究证实了卵巢内存在一个完整的 白介素1(IL-1)系统，充满配体、受体和 受体拮抗剂。这项新提议试图检验这样一个假设： 卵巢内IL-1可能在排卵过程中起中介作用。 更具体地说，它假设卵巢内IL-1β(的 膜-间质或驻留巨噬细胞起源)可构成 促性腺激素诱导排卵的介体，一种效应物 能够协调和放大排卵的关键成分 卡斯卡德。对这一假说的支持可以从1) 人绒毛膜促性腺激素对IL-1β诱导排卵作用的实验研究 在小鼠和人卵巢中的转录本，2)观察 IL-1β体外激活几种已建立的细胞因子 排卵前级联反应的成分[例如胶原酶的产生， 蛋白多糖/透明质酸的生产和前列腺素的生物合成]， 3)IL-1β体外诱导能力的文献 排卵，促进卵母细胞成熟，以及允许受精，以及 随后的早期胚胎发育。因此，中期 促性腺激素激增诱导的卵巢内IL-1β可能构成 与排卵有关的调节级联反应的中心。这样的一个 这一概念与排卵可能构成 一个类似炎症的过程以及对IL-1是一种 公认的炎症介质。为了检验上述假设， 进一步了解卵巢内IL-1系统的工作原理， 并为IL-1在正常人体内的作用提供无可辩驳的体内证据 卵巢生理、体内、体外一系列互补 提出了实验方案。直接评估潜在的关联性 IL-1对排卵过程、体内外源性IL-1能力的影响 导致排卵(导致受精和早期胚胎 将评估PMSG诱导的未成熟大鼠的发育)，并 特色化的。此外，一种特异性的重组IL-1受体拮抗剂 将在体内评估其阻断IL-1或促性腺激素的能力- 诱导排卵(目标I)。我们还将高度重视 卵巢IL-1受体亚型(I和II)的鉴定 它们的细胞定位、排卵期表达和激素 监管。在这方面，相应基因的测量 以及推测的蛋白质产品的成绩单将是 已执行(目标II)。对于IL-1受体也有类似的研究。 拮抗剂认识到其作为网络决定因素的作用 卵巢内IL-1活性(AIM III)。最后，细胞机制(S) 通过IL-1刺激卵巢前列腺素的生物合成 发言(目标四)。这项调查的长期目标是 发展对分子机制的更好理解(S) IL-1可能参与排卵过程。这种洞察力可能会导致 在阐明一些分子事件的基础上 排卵过程中，生殖副作用的描绘 系统性抗IL-1疗法(目前处于早期临床试验)， 并在可能改进的促进生育率的战略中 它的控制力。

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.