miR-132-3p Modulates DUSP9-Dependent p38/JNK Signaling Pathways to Enhance Inflammation in the Amnion Leading to Labor

Abstract

Labor is a process of inflammation and hormonal changes involving both fetal and maternal compartments. MicroRNA-132-3p (miR-132-3p) has been reported to be involved in the development of inflammation-related diseases. However, little is known about its potential role in labor onset. This study aimed to explore the mechanism of miR-132-3p in amnion for labor initiation. In the mouse amnion membranes, the expression of miR-132-3p was found to increase gradually during late gestation. In human amniotic epithelial cell line (WISH), upregulation of miR-132-3p was found to increase proinflammatory cytokines and cyclooxygenase 2 (COX2) as well as prostaglandin E2 (PGE2), which was suppressed by miR-132-3p inhibitor. Dual-specificity phosphatase 9 (DUSP9) was identified as a novel target gene of miR-132-3p, which could be negatively regulated by miR-132-3p. DUSP9 was present in the mouse amnion epithelial cells, with a decrease in its abundance at 18.5 days post coitum (dpc) relative to 15.5 dpc. Silencing DUSP9 was found to facilitate the expression of proinflammatory cytokines and COX2 as well as PGE2 secretion in WISH cells, which could be attenuated by p38 inhibitor SB203580 or JNK inhibitor SP600125. Additionally, intraperitoneal injection of pregnant mice with miR-132-3p agomir not only caused preterm birth, but also promoted the abundance of COX2 as well as phosphorylated JNK and p38 levels, and decreased DUSP9 level in mouse amnion membranes. Collectively, miR-132-3p might participate in inflammation and PGE2 release via targeting DUSP9-dependent p38 and JNK signaling pathways to cause preterm birth.

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“…On the contrary, as NLRP3 concentration increased, the expression of this miRNA decreased in abnormal growth and SGA pregnancies (p-values = 0.007 and 0.012, respectively). Mainly known for its role in inflammation, miR-132-3p has been recently implicated in APOs such as pre-term birth [52], pre-eclampsia [53], and gestational diabetes [54]. Besides, LPS-induced upregulation of this miRNA was found to promote NLRP3 activation and pyroptosis [55].…”

“…The custom pool was made for the analysis of 14 target miRNAs (hsa-miR-101-3p, hsa-miR-106a-5p, hsa-miR-125a-5p, hsa-miR-126-3p, hsa-miR-132-3p, hsa-miR-137, hsa-miR-146a-5p, hsa-miR-155-5p, hsa-miR-195-5p, hsa-miR-210-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-223-5p, and hsa-miR-34a-5p), 2 endogenous controls (RNU48 and U6-RNA), and 1 exogenous control (ath-miR159a). These miRNAs were selected on the basis of the existing literature [52,[58][59][60][61][62][63] and of previous studies conducted in our lab [64][65][66], showing their responsiveness to pro-inflammatory stimuli, and validated through the Non-coding RNAs in Inflammation (ncRI) database [67].…”