Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 201203, People's Republic of China.
Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China.
J Reprod Immunol. 2022 Jun;151:103623. doi: 10.1016/j.jri.2022.103623. Epub 2022 Apr 12.
Appropriate decidualization is of great importance for embryo implantation, placental development and successful pregnancy. Although it has been well-acknowledged that decidualization relies on activation of progesterone-mediated signaling pathway, the exact mechanisms have not been elucidated. Here, we demonstrated that both IL-27 and IL27RA were highly expressed in decidua than those in endometrium during secretory phase. Estrogen plus progesterone significantly upregulated the expression of IL-27 and IL-27RA in endometrium stromal cells (ESCs). In addition, inhibiting IL-27 signaling with IL-27 neutralization antibody (anti-IL-27) suppressed the expression of decidualization-related molecules, receptors of estrogen (gene coded by ESR) and progesterone (PGR) induced by cAMP or estrogen plus progesterone. Similar results were obtained from Il27ra (knockout of Il27ra) female mice. Moreover, knockout of Il27ra did not affect the estrus cycle and folliculogenesis in mice but reduced implantation rate with the impairing decidualization. Mechanistically, IL-27 upregulated the expression of ESR1, ESR2 and PGR in ESCs and DSCs, as well as the phosphorylation level of STAT3. In the presence of estrogen plus progesterone, treatment with ESCs with anti-IL-27 inhibited the activation of STAT3. Also, the expression of ESR, PGR was decreased in Il27ra mice. In conclusion, these findings demonstrate that IL-27 upregulated by estrogen and progestogen promotes decidualization possibly through a STAT3-dominant pathway.
适当的蜕膜化对于胚胎着床、胎盘发育和成功妊娠至关重要。尽管人们已经充分认识到蜕膜化依赖于孕激素介导的信号通路的激活，但确切的机制尚未阐明。在这里，我们发现在分泌期，蜕膜中 IL-27 和 IL27RA 的表达均高于子宫内膜。雌激素加孕激素显著上调子宫内膜基质细胞（ESCs）中 IL-27 和 IL-27RA 的表达。此外，用 IL-27 中和抗体（抗 IL-27）抑制 IL-27 信号通路，抑制 cAMP 或雌激素加孕激素诱导的蜕膜化相关分子、雌激素受体（ESR，由基因 ESR 编码）和孕激素受体（PGR）的表达。来自 Il27ra（Il27ra 敲除）雌性小鼠的类似结果也得到了证实。此外，Il27ra 的敲除并不影响小鼠的发情周期和卵泡发生，但降低了着床率，并损害了蜕膜化。在机制上，IL-27 上调了 ESCs 和 DSCs 中 ESR1、ESR2 和 PGR 的表达以及 STAT3 的磷酸化水平。在雌激素加孕激素存在的情况下，用抗 IL-27 处理 ESCs 抑制了 STAT3 的激活。此外，Il27ra 小鼠的 ESR 和 PGR 表达减少。总之，这些发现表明，雌激素和孕激素上调的 IL-27 通过 STAT3 优势途径促进蜕膜化。
