Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth

Ozlem Guzeloglu-Kayisli; Nihan Semerci; Xiaofang Guo; Kellie Larsen; Asli Ozmen; Sefa Arlier; Duygu Mutluay; Chinedu Nwabuobi; Bradley Sipe; Irina Buhimschi; Catalin Buhimschi; Frederick Schatz; Umit A Kayisli; Charles J Lockwood

doi:10.1073/pnas.2010282118

Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth

Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2010282118. doi: 10.1073/pnas.2010282118.

Affiliations

¹ Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612; ozlem2@usf.edu cjlockwood@usf.edu.
² Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612.
³ Department of Obstetrics and Gynecology, University of Illinois College of Medicine, Chicago, IL 60612.

Abstract

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.

Keywords: FKBP51; decidual cells; maternal stress; preterm birth; progesterone receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Mice
Models, Animal
Pregnancy
Premature Birth*
Protein Binding
RNA, Messenger / genetics
Receptors, Progesterone / metabolism*
Stress, Physiological*
Tacrolimus Binding Proteins / genetics
Tacrolimus Binding Proteins / metabolism*

Substances

RNA, Messenger
Receptors, Progesterone
Tacrolimus Binding Proteins
tacrolimus binding protein 5