IL-33/PIBF1信号通路异常抑制子宫内膜间质细胞蜕膜化导致胚胎反复种植失败的机制

子宫内膜间质细胞(HESC)蜕膜化缺陷是导致胚胎反复种植失败(RIF)的关键因素。前期研究发现：HESC中PIBF1/IL-6低表达抑制细胞增殖及蜕膜化；RIF患者分泌中期IL-33水平显著降低，与PIBF1一致；敲低T-HESC及HESC中IL-33后PIBF1、IL-6及增殖与蜕膜化的标志物表达均降低，并可逆转；而敲低其受体ST2L，PIBF1及IL-6表达亦降低，过表达IL-33后不能恢复；IL-33条件敲除小鼠动情期子宫内膜以上因子表达均低下。由此推测，低水平的IL-33通过PIBF1/IL-6信号通路抑制子宫内膜间质细胞增殖和蜕膜化进而影响子宫内膜容受性。本项目拟系统研究IL-33等分子标志物与RIF的相关性；明晰IL-33调控蜕膜化的作用；揭示IL-33/ST2调控PIBF1信号通路诱导HESC增殖及蜕膜化的机制；探索以干预IL-33相关信号通路为核心防治胚胎种植失败的新策略。

Defective decidualization of the human endometrial stromal cell (HESC) is the crux of recurrent implantation failure (RIF). Our preliminary results showed that the inferior expression of PIBF1/IL-6 in mid-secretory HESC in RIF patients results in suppressed cell proliferation, which is closely related to defective decidualization. The level of IL-33 in the RIF patients, which is the same as that of PIBF1, was down-regulated as well. Knockdown the expression of IL-33, the expression of PIBF1, IL-6 and the markers of HESC proliferation and decidualization would decrease but could be rescued. Knockdown the expression of its receptor, ST2L, the expression of PIBF1, IL-6 was decreased as well and forced expression of IL-33 could not rescue the expression of PIBF1 and IL-6. What’s more, the expression of PIBF1, IL-6 and markers of HESC decidualization was down-regulated in the endometrium of IL-33 cKO mice during the estrus. The scientific issue focused on in this project is the mechanism by which abnormal IL-33/PIBF1 signaling pathway inhibits the decidualization of endometrial stromal cells, thus causes recurrent implantation failure. We are about to systematically clarify the correlation between RIF and the potential markers like IL-33 and PIBF1.etc, to elucidate the role and the mechanism of IL-33/ST2 in regulating HESC proliferation and the following decidualization via regulating PIBF1 signaling pathway, to investigate and formulate a new strategy to prevent the failure of embryo implantation by interfering IL-33 related signaling pathways.