期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：11
页码：1
DOI：10.1073/pnas.2010282118
出版社：The National Academy of Sciences of the United States of America
摘要：Depression and posttraumatic stress disorder increase the risk of idiopathic preterm birth (iPTB); however, the exact molecular mechanism is unknown. Depression and stress-related disorders are linked to increased FK506-binding protein 51 (FKBP51) expression levels in the brain and/or FKBP5 gene polymorphisms. Fkbp5 -deficient ( Fkbp5 −/− ) mice resist stress-induced depressive and anxiety-like behaviors. FKBP51 binding to progesterone (P4) receptors (PRs) inhibits PR function. Moreover, reduced PR activity and/or expression stimulates human labor. We report enhanced in situ FKBP51 expression and increased nuclear FKBP51-PR binding in decidual cells of women with iPTB versus gestational age-matched controls. In Fkbp5 / mice, maternal restraint stress did not accelerate systemic P4 withdrawal but increased Fkbp5 , decreased PR, and elevated AKR1C18 expression in uteri at E17.25 followed by reduced P4 levels and increased oxytocin receptor ( Oxtr ) expression at 18.25 in uteri resulting in PTB. These changes correlate with inhibition of uterine PR function by maternal stress–induced FKBP51. In contrast, Fkbp5 −/− mice exhibit prolonged gestation and are completely resistant to maternal stress–induced PTB and labor-inducing uterine changes detected in stressed Fkbp5 / mice. Collectively, these results uncover a functional P4 withdrawal mechanism mediated by maternal stress–induced enhanced uterine FKBP51 expression and FKPB51-PR binding, resulting in iPTB.
