Estradiol Suppresses TLR4-triggered Apoptosis of Decidual Stromal Cells and Drives an Anti-inflammatory T H 2 Shift by Activating SGK1

作者：Yiyun Lou, Minhao Hu, Qijing Wang, Mu Yuan, Ning Wang, Le Fang, Lejun Li, Shisi Huang, Liya Wang, Xiangrong Xu, Fan Jin · 发表于：International Journal of Biological Sciences · 年份：2017 · DOI：10.7150/ijbs.18278 · 被引用次数：47 · 研究领域：Reproductive System and Pregnancy、Pregnancy and preeclampsia studies、Reproductive Physiology in Livestock

A pro-inflammatory cytokine profile at the feto-maternal interface may predispose immune maladaptation notably in early miscarriages.We investigated the involvement of estradiol (E 2 )-activated serum-glucocorticoid regulated kinase 1 (SGK1) in preserving the tolerogenic and pro-survival intrauterine microenvironment beneficial to gestation maintenance.Decidual SGK1 was down-regulated in early miscarriage, consistent with the lower serum E 2 concentration seen in pregnancy loss.Lipopolysaccharide (LPS)/Toll-like receptors 4 (TLR4) signaling induced apoptosis and the pro-inflammatory T helper type (T H ) 1 response of decidual stromal cells (DSCs) were associated with miscarriage.SGK1 activation was suppressed by LPS/TLR4 signaling and would be rescued by E 2 administration via the PI3K signaling pathway in DSCs.SGK1 activation attenuated TLR4-mediated cell apoptosis, while promoting cell viability of DSCs by up-regulating the pro-survival genes BCL2 and XIAP, and enhancing the phosphorylation of FOXO1.Furthermore, E 2 -induced SGK1 activation reduced the secretion of pro-inflammatory T H 1 cytokines, and promoted the generation of T H 2 cytokines and elevated IRF4 mRNA and protein levels in LPS-incubated DSCs.Pharmacologic inhibition of SGK1 or suppression by small interfering (si) RNA increased the phosphorylation and nuclear translocation of NF-κB to reverse the pro-T H 2 and anti-inflammatory effects of E 2 pretreatment, leading to compromised pregnancy.These findings sugg...