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Int J Biol Sci 2017; 13(4):434-448. doi:10.7150/ijbs.18278 This issue Cite

Research Paper

Estradiol Suppresses TLR4-triggered Apoptosis of Decidual Stromal Cells and Drives an Anti-inflammatory T_H2 Shift by Activating SGK1

Yiyun Lou^{1, 2*}, Minhao Hu^1*, Qijing Wang^1*, Mu Yuan^1*, Ning Wang¹, Fang Le¹, Lejun Li¹, Shisi Huang¹, Liya Wang¹, Xiangrong Xu¹, Fan Jin^1✉

1. Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics, Ministry of Education, Key Laboratory of Women's Reproductive Health of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
2. Department of Gynaecology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, 310007, China.
* These authors contributed equally to this work.

✉ Corresponding author: Dr. Fan Jin Ph.D., M.D. Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics, Ministry of Education, Key Laboratory of Women's Reproductive Health of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China. Tel: +86 571 87013891; Fax: +86 571 87061878; E-mail: jinfanedu.cn. More

Abstract

A pro-inflammatory cytokine profile at the feto-maternal interface may predispose immune maladaptation notably in early miscarriages. We investigated the involvement of estradiol (E₂)-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 E₂ 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 E₂ 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, E₂-induced SGK1 activation reduced the secretion of pro-inflammatory T_H1 cytokines, and promoted the generation of T_H2 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_H2 and anti-inflammatory effects of E₂ pretreatment, leading to compromised pregnancy. These findings suggest that the E₂-mediated SGK1 activation suppressed LPS-mediated apoptosis and promoted the anti-inflammatory T_H2 responses in DSCs, ultimately contributing to a successful pregnancy.

Keywords: miscarriage, SGK1, E₂, DSCs, inflammation, apoptosis, T_H2 cytokine

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