Affiliation:
1. Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
2. Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
3. Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, China
Abstract
Abstract
Human blastocyst nidation in the uterus and successful pregnancy require coordinated endometrial expression of estrogen receptor (ER)-α, progesterone receptors (PR)-A and -B and the gap junction protein, connexin (Cx)43. Our prior work established that inflammation associated with conditions of reduced fecundity, particularly endometriosis, can perturb eutopic decidual function. In the current studies, we have modeled endometrial decidualization in primary human endometrial stromal cell cultures derived from normal controls (NESC) and from the eutopic endometria of women with endometriosis (EESC) to test the hypothesis that a proinflammatory cytokine, interleukin (IL)-1β, can disrupt stromal cell differentiation. The cells were grown under a standard protocol with hormones (10 nM 17β-estradiol, 100 nM progesterone and 0.5 mM dibutyryl cAMP) for up to 7 days in the absence or presence of IL-1β. Time-course experiments showed that IL-1β compromised decidual function in both NESC and EESC, which was accompanied by rapid phosphorylation of ER-α, PR and Cx43 and their cellular depletion. Inhibition of the extracellular signal-regulated kinase (ERK)1/2 pathway by a selective pharmacological blocker (PD98059) or siRNA interference, or the addition of hormones themselves, blocked the phosphorylation of ERK mediators; increased the production of steroid receptors, Cx43, prolactin, insulin-like growth factor binding protein-1 (IGFBP)-1 and vascular endothelial growth factor (VEGF) and accelerated the differentiation. The results indicate that inhibition of IL-1β can enhance decidualization in NESC and EESC in vitro. Strategies to interfere with this pathway might be implemented as an in vivo approach to enhance fertility in women with endometriosis and, potentially, other inflammatory pathologies.
Funder
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Publisher
Oxford University Press (OUP)
Subject
Cell Biology,Developmental Biology,Obstetrics and Gynecology,Genetics,Molecular Biology,Embryology,Reproductive Medicine
Cited by
19 articles.
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