Prolonged pregnancy in women is associated with attenuated myometrial expression of progesterone receptor co-regulator Krüppel-like Factor 9.

Abstract

Late-term pregnancy may lead to maternal and neonatal morbidity and mortality. Mice null for the progesterone receptor co-regulator Krüppel-like Factor 9 (KLF9) exhibit delayed parturition and increased incidence of neonatal deaths. Our aim is to evaluate the contribution of myometrial KLF9 to human parturition. Myometrial biopsies were obtained from women with term (>37 to ≤41 wk) and late-term (>41 wk) pregnancies during cesarean delivery and assessed for gene and protein expression. Human myometrial cells transfected with nontargeting or KLF9 small interfering RNAs (siRNA) were treated with the progesterone antagonist RU486 and analyzed for pro-inflammatory chemokine/cytokine gene expression. The study took place in a University-affiliated tertiary care hospital and University research laboratory. Term patients (n = 8) were in spontaneous active labor whereas late-term patients (n = 5) were either in or were induced to active labor, prior to elective cesarean delivery. Steroid hormone receptor, contractility, and inflammation-associated gene expression in myometrial biopsies and in siKLF9-transfected, RU486-treated human myometrial cells was associated with KLF9 expression levels. Myometrium from women with late-term pregnancy showed lower KLF9, total PGR, and PGR-A/PGR-B isoform expression. Transcript levels of select chemokines/cytokines were up- (CSF3, IL1, IL12A, TGFB2) and down- (CCL3, CCL5, CXCL1, CXCL5, IL15) regulated in late-term relative to term myometrium. Knock-down of KLF9 expression in RU486-treated human myometrial cells modified the expression of PGR and labor-associated cytokines, relative to control siRNA-treated cells. Myometrial KLF9 may contribute to the onset of human parturition through its regulation of PGR expression and inflammatory signaling networks.