Liu Ling, Zhang Yan, Wang Yankui, Peng Wei, Zhang Ning, Ye Yuanhua
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China.
J Obstet Gynaecol Res. 2018 Mar;44(3):463-473. doi: 10.1111/jog.13549. Epub 2017 Dec 14.
Pre-eclampsia (PE) is a pregnancy complication characterized by new onset maternal hypertension and proteinuria. Its underlying mechanisms are unclear. This study investigated the relationship between progesterone and endoplasmic reticulum stress (ERS) associated apoptosis induced by interleukin (IL)-1β via the glucose regulated protein 78 (GRP78)/protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP-homologous protein (CHOP) pathway in BeWo cells.
Venous blood and placental tissues were collected from PE patients, normal pregnancy and preterm delivery cases, respectively. Progesterone serum levels were detected by enzyme-linked immunosorbent assay and ERS-related protein expression in placentas was examined by immunohistochemistry, reverse transcriptase-polymerase chain reaction and Western blot. BeWo cells were stimulated by IL-1β to induce ERS associated apoptosis in vitro. The apoptotic rate was measured by flow cytometry. The mechanism of progesterone acting on IL-1β induced ERS associated apoptosis was investigated by reverse transcriptase-polymerase chain reaction, Western blot and PERK small interfering RNA, with RU486 used as a receptor inhibitor.
PE patients exhibited decreased serum levels of progesterone and activated ERS and increased ERS-related protein expression. IL-1β could induce ERS and associated cell apoptosis by activating the GRP78/PERK/CHOP signal pathway, which could be inhibited by progesterone. PERK could be upregulated and phosphorylation activated in ERS. The protective effects of progesterone could be attenuated by RU486.
IL-1β could induce ERS associated cell apoptosis by activating the GRP78/PERK/CHOP signal pathway in BeWo cells and may play an important role in PE occurrence. Progesterone levels were decreased in patients with PE and seemed to have a protective effect by inhibiting ERS associated cell apoptosis.
子痫前期（PE）是一种以新发母体高血压和蛋白尿为特征的妊娠并发症。其潜在机制尚不清楚。本研究通过葡萄糖调节蛋白78（GRP78）/蛋白激酶RNA样内质网激酶（PERK）/C/EBP同源蛋白（CHOP）途径，研究孕酮与白细胞介素（IL）-1β诱导的内质网应激（ERS）相关细胞凋亡之间的关系，该研究以BeWo细胞为研究对象。
分别从PE患者、正常妊娠和早产病例中采集静脉血和胎盘组织。采用酶联免疫吸附测定法检测血清孕酮水平，采用免疫组织化学、逆转录聚合酶链反应和蛋白质免疫印迹法检测胎盘组织中ERS相关蛋白的表达。在体外，用IL-1β刺激BeWo细胞以诱导ERS相关细胞凋亡。采用流式细胞术测定细胞凋亡率。采用逆转录聚合酶链反应、蛋白质免疫印迹法和PERK小干扰RNA，以RU486作为受体抑制剂，研究孕酮作用于IL-1β诱导的ERS相关细胞凋亡的机制。
PE患者血清孕酮水平降低，ERS激活，ERS相关蛋白表达增加。IL-1β可通过激活GRP78/PERK/CHOP信号通路诱导ERS和相关细胞凋亡，而孕酮可抑制该过程。在ERS中，PERK可上调并磷酸化激活。RU486可减弱孕酮的保护作用。
IL-1β可通过激活BeWo细胞中的GRP78/PERK/CHOP信号通路诱导ERS相关细胞凋亡，可能在PE的发生中起重要作用。PE患者孕酮水平降低，似乎通过抑制ERS相关细胞凋亡发挥保护作用。
