PDF(Pubmed)
Abstract：
Implantation and maintenance of pregnancy involve intricate immunological processes that enable the developing fetus to coexist with the maternal immune system. Progesterone, a critical hormone during pregnancy, is known to promote immune tolerance and prevent preterm labor. However, the mechanism by which progesterone mediates these effects remains unclear. In this study, we investigated the role of the non-classical progesterone receptor membrane component 1 (PGRMC1) in progesterone signaling at the maternal-fetal interface. Using JEG3 cells, a trophoblast model cell line, we observed that progesterone stimulation increased the expression of human leukocyte antigen-C (HLA-C) and HLA-G, key molecules involved in immune tolerance. We also found that progesterone upregulated the expression of the transcription factor ELF3, which is known to regulate trophoblast-specific HLA-C expression. Interestingly, JEG3 cells lacked expression of classical progesterone receptors (PRs) but exhibited high expression of PGRMC1, a finding we confirmed in primary trophoblasts by mining sc-RNA seq data from human placenta. To investigate the role of PGRMC1 in progesterone signaling, we used CRISPR/Cas9 technology to knockout PGRMC1 in JEG3 cells. PGRMC1-deficient cells showed a diminished response to progesterone stimulation. Furthermore, we found that the progesterone antagonist RU486 inhibited ELF3 expression in a PGRMC1-dependent manner, suggesting that RU486 acts as a progesterone antagonist by competing for receptor binding. Additionally, we found that RU486 inhibited cell invasion, an important process for successful pregnancy, and this inhibitory effect was dependent on PGRMC1. Our findings highlight the crucial role of PGRMC1 in mediating the immunoregulatory effects of progesterone at the maternal-fetal interface.
摘要：
妊娠的植入和维持涉及复杂的免疫过程，使发育中的胎儿能够与母体免疫系统共存。孕酮,怀孕期间的一种关键激素，已知促进免疫耐受和预防早产。然而,孕酮介导这些作用的机制尚不清楚.在这项研究中,我们研究了非经典孕激素受体膜成分1(PGRMC1)在母胎界面孕激素信号传导中的作用.使用JEG3细胞，滋养层细胞模型细胞系,我们观察到孕激素刺激增加了人类白细胞抗原-C（HLA-C）和HLA-G的表达，参与免疫耐受的关键分子。我们还发现孕酮上调转录因子ELF3的表达，已知该转录因子可调节滋养层特异性HLA-C表达。有趣的是,JEG3细胞缺乏经典孕激素受体（PR）的表达，但表现出PGRMC1的高表达，这是我们通过从人类胎盘中挖掘sc-RNAseq数据在原代滋养细胞中证实的发现。探讨PGRMC1在孕酮信号中的作用,我们使用CRISPR/Cas9技术在JEG3细胞中敲除PGRMC1。PGRMC1缺陷细胞对孕酮刺激的反应减弱。此外，我们发现，孕酮拮抗剂RU486以依赖PGRMC1的方式抑制ELF3的表达，表明RU486通过竞争受体结合而充当孕酮拮抗剂。此外,我们发现RU486抑制细胞侵袭，成功怀孕的重要过程，这种抑制作用依赖于PGRMC1。我们的发现强调了PGRMC1在介导孕酮在母胎界面的免疫调节作用中的关键作用。
