LMU Munich, University Hospital, Department of Obstetrics and Gynaecology, Marchioninistr. 15, 81377 Munich, Germany; Department of Emergency, Affiliated Hospital of Southwest Medical University, Southwest Medical University, Taiping Rd. 25, Luzhou 646100, China.
LMU Munich, University Hospital, Department of Obstetrics and Gynaecology, Marchioninistr. 15, 81377 Munich, Germany; Department of Gynecology and Obstetrics, Zhongshan Hospital, Fu Dan University School of Medicine, Fenglin Rd. 180, Shanghai, 200030, China.
J Reprod Immunol. 2020 Nov;142:103210. doi: 10.1016/j.jri.2020.103210. Epub 2020 Oct 1.
Prostaglandin E2 (PGE2), an inflammatory mediator, modulates cytokines, regulates immune responses in reproductive processes and stimulates inflammatory reactions via the prostaglandin E2 receptor 2 (EP2). However, the regulatory effects of EP2 signaling on trophoblasts and its role in unexplained recurrent miscarriage (uRM) remains unclear.
A total of 19 placentas from patients with a history of more than two consecutive pregnancy losses of unknown cause (uRM group) and placentas of 19 healthy patients following a legal termination of their pregnancy were used for PGE2 receptor (EP1, EP2 and EP4) expression analyses via immunohistochemistry. Double immunofluorescence was also used to identify EP2 expressing cells in the decidua. Finally, HTR-8/SVneo cells were used to clarify the role of EP2 in in vitro experiments.
The expression of EP2 and EP4 was found to be reduced in the syncytiotrophoblast and decidua of uRM patients. A selective EP2 receptor antagonist (PF-04,418,948) reduced the proliferation and secretion of ß-hCG, inhibited interleukin -6 (IL-6) and interleukin-8 (IL-8) and up-regulated the production of the tumor necrosis factor-α (TNF-α) and plasminogen activator inhibitor type 1 (PAI-1) in HTR-8/SVneo cells in vitro.
PGE2-EP2 signaling pathway may represent a novel therapy option for uRM. The involvement of EP2 in uRM acts perhaps via inflammatory cytokines and indicates that the PGE2-EP2 signaling pathway might represent an unexplored etiology for uRM.
前列腺素 E2（PGE2）作为一种炎症介质，可调节细胞因子，调节生殖过程中的免疫反应，并通过前列腺素 E2 受体 2（EP2）刺激炎症反应。然而，EP2 信号对滋养层的调节作用及其在不明原因复发性流产（uRM）中的作用尚不清楚。
共使用 19 例有两次以上不明原因连续妊娠丢失（uRM 组）病史的患者胎盘和 19 例因合法终止妊娠的健康患者胎盘进行 PGE2 受体（EP1、EP2 和 EP4）表达分析，采用免疫组织化学法。还使用双重免疫荧光法鉴定蜕膜中表达 EP2 的细胞。最后，使用 HTR-8/SVneo 细胞阐明 EP2 在体外实验中的作用。
发现 uRM 患者的合体滋养层和蜕膜中 EP2 和 EP4 的表达减少。选择性 EP2 受体拮抗剂（PF-04418948）减少了β-hCG 的增殖和分泌，抑制了白细胞介素-6（IL-6）和白细胞介素-8（IL-8），并上调了肿瘤坏死因子-α（TNF-α）和纤溶酶原激活物抑制剂 1（PAI-1）在 HTR-8/SVneo 细胞中的产生。
PGE2-EP2 信号通路可能是 uRM 的一种新的治疗选择。EP2 在 uRM 中的作用可能是通过炎症细胞因子发挥的，这表明 PGE2-EP2 信号通路可能是 uRM 的一种未被探索的病因。
