IL-27通过诱导异位灶微环境IL-10+Th17细胞分化促进内异症进展的分子机制

It has been reported the abnormal local immune microenvironment in abdominal from women with endometriosis can not effectively remove endometrial stromal cells (ESC) of the ectopic foci.In contrast, it can promote the growth and implantation of ESC. Recent studies suggest that IL-10+Th17 cells have regulatory function. We found that the peritoneal fluid (PF) of patients with endometriosis had high levels of Th17 cells and IL-17A. Moreover, IL-10 level of PF in III-IV patients was higher than that in I-II patients. The results suggested that the local microenvironment of women with endometriosis present a coexistence state of pro-inflammatory and tolerance. The initial stage of this disease, a dominant position is pro-inflammatory. On the contrary, such advantage tends to tolerance during the latter of endometriosis. Further studies showed that ESC of ectopic foci highly expressed IL-27. After co-culture with macrophage, it could induce na?ve T differentiate to IL-10+Th17 cells. However, the molecular mechanisms and the roles in the development of endometriosis are unclear. Therefore, takeing advantege of in vitro trials for imitating the abdominal microenvironment in endometriosis and in vivo animal experiments, our study intends to investigate the downstream signal pathways and transcription factors which are involved in ESC and macrophage-derived IL-27 on IL-10+Th17 cells differentiation, to further explore whether these Th17 cells promote the progress of endometriosis by secreting IL-17A and IL-10, and to study the pathological mechanisms.This project will provide a new direction for researching the pathogenesis of endometriosis, and the scientific basis for finding new strategies in the prevention and treatment of endometriosis.

研究显示子宫内膜异位症（简称内异症）患者盆腹腔局部免疫微环境异常，不仅不能清除异位灶内膜间质细胞（ESC）且促进其生长种植。近来研究提示IL-10+Th17细胞具有调节功能。我们发现内异症患者腹腔液存在高水平Th17细胞及IL-17A，III-IV期患者有更高水平IL-10，提示随疾病进展，呈现促炎和耐受并存并偏向耐受的过程。我们新近发现异位灶ESC高表达IL-27，与巨噬细胞共培养后可诱导naive T向IL-10+Th17细胞分化，但分子机制及其在内异症发展中的作用尚不清楚。故本课题以体外模拟内异症盆腹腔微环境和体内动物实验为研究手段，拟研究ESC和巨噬细胞来源的IL-27通过何种信号和下游转录因子介导这群Th17细胞分化，进一步解析这群细胞是否通过IL-17A和IL-10促进内异症进展及病理机制。本课题将为内异症发病机理研究提供新的研究方向，为寻找防治内异症的新策略提供科学依据。

子宫内膜异位症是一种雌激素依赖性炎症性疾病。报道显示内异症患者抗炎细胞因子IL-10增加。Th17细胞产生IL-10是限制自身免疫和炎症反应的关键。然而，这群IL-10+Th17细胞分化机制尚不明确。我们的研究发现，伴随疾病进展，内异症患者腹腔液中IL-10+Th17细胞显著升高，同时伴有细胞因子IL-27、IL-6和TGF-β水平升高。相对于外周血CD4+T细胞，子宫内膜CD4+T细胞高表达IL-27受体，尤其是来源于内异症异位灶内膜。在外环境（如二噁英）和内环境（雌激素等）因素的调控下，巨噬细胞和子宫内膜间质细胞（ESC）来源的IL-27可在体外和体内诱导Th17细胞产生IL-10。这个过程可能与c-Maf和RORγt交互作用，及其下游分子Blimp-1有关。反过来，这群IL-10+Th17细胞促进异位灶生长和种植，加速内异症进展。这些结果表明，作为异位灶免疫耐受的一个重要调节因子，IL-27诱导IL-10+Th17细胞分化，进而促进异位灶的快速生长和种植。我们的研究发现同时干预促炎性细胞因子IL-17A和抗炎性细胞因子IL-10的抗子宫内膜异位症的效果更佳。这些研究诠释了抗炎性细胞因子在子宫内膜异位症进展中的作用和分子机制，及其干预在抗子宫内膜异位症中的潜在价值。