Normally physiological activity of ovary decides the mammalian reproductive performance. Millions of follicles constitute the ovarian core structure. The regular, cyclic menstrual cycles depend on the gonadotrophin-controlled follicle development. Beyond gonadotrophin, kinds of growth factors coordinately participate in the regulation of folliculogenesis process (Richards and Ascoli, 2018). The proper expression of autocrine/paracrine factors are vital for the maintenance of dynamically changed follicular microenvironment. Aberrant expression of autocrine/paracrine factors will disrupt the balance of follicular microenvironment and subsequently cause the follicle development arrest. Interleukin-1 (IL-1), a member of interleukin family, is a well-known growth factor involved in innate immunity system and inflammation (Moorlag et al., 2018). To date, two major IL-1 cytokines, IL-1α and IL-1β, have been identified in eukaryote to induce a variety of proinflammatory factors expression (Boraschi et al., 2018). In mammalian ovary, IL-1 is extensively expressed in various follicular cell layers. Interestingly, the expression level of IL-1 mRNA is dynamically changed depending on the estrus cycle phase (Gerard et al., 2004). In mouse ovary, the initiation of IL-1α and IL-1β expression is detected in oocyte and theca cell of growing follicle. Before ovulation, the transcript levels of IL-1α and IL-1β in cumulus cell are increased after luteinizing hormone (LH) surge (Simon et al., 1994). Similarly, a recent study on transcriptomic changes of periovulatory human granulosa cells confirms the upregulation of IL-1 expression levels after LH surge (Poulsen et al., 2020). Besides, previous study has demonstrated that IL-1β stimulates progesterone production via upregulating StAR expression in human granulosa-lutein cells (Di et al., 2018). Moreover, IL-1 level is also associated with women reproductive aging (Hurwitz et al., 2010). These studies indicate the involvement of IL-1 on the regulation of folliculogenesis. Furthermore, past decade of studies on IL-1 in human reproductive system have demonstrated that aberrant expression of IL-1 is highly correlated with the occurrence of several reproductive endocrinology diseases, like polycystic ovary syndrome (PCOS) (Popovic et al., 2019). A comparative study has been reported that the expression of IL-1 is enhanced in PCOS patients (Adams et al., 2016). Moreover, a very recent study finds that the balance of follicular fluid microenvironment is disrupted and several immune factor levels is increased, including IL-1β (Liu et al., 2021). Although various clinical studies have demonstrated the correlation between IL-1 and PCOS, the detailed molecular pathogenic mechanism remains to be elucidated.

The LH-triggered ovulation causes the huge inner physiological and architectural changes of follicle. Oocyte and the surrounding cumulus cell constitute the cumulus-oocyte complex (COC), which is the main structural unit of follicle. After the LH surge, ovulation-related gene expression will be increased and subsequently mediates the ovulation process, including COC expansion, meiosis resumption and hormone synthesis et al. (Poulsen et al., 2020). Several endocrine factors have been reported to participate in the regulation of ovulation (Chang et al., 2016). Among these endocrine factors, prostaglandin E2 (PGE2) plays an important role in mediating oocyte maturation and ovulation. The production of PGE2 relies on the cyclooxygenase (COX) enzyme catalysis effect. Two COX isoforms have been identified, including COX-1 and COX-2 (Smith et al., 2000). Animal studies have demonstrated that Cox-2-null female mice exhibit multiple female reproductive defects whereas Cox-1 deletion mice have the normal reproductive performance, implying the essential role of COX-2 in the maintenance of female fertility (Langenbach et al., 1995; Lim et al., 1997). The studies on inflammatory disease reveal that PGE2 production is increased when cells are exposed to IL-1 (Dinarello, 2002). In female reproductive system, although the regulatory effects of IL-1 on PGE2 production has been reported (Narko et al., 1997), the underlying mechanism remains to be elucidated. In the present study, we sought to explore the cellular effects of IL-1 on the production of PGE2, as well as its underlying molecular mechanism in human granulosa cells.