TY - JOUR
T1 - Reciprocal feedback between miR-181a and E2/ERα in myometrium enhances inflammation leading to labor
AU - Gao, Lu
AU - Wang, Gang
AU - Liu, Wei Na
AU - Kinser, Holly
AU - Franco, Hector L.
AU - Mendelson, Carole R.
N1 - Publisher Copyright:
© 2016 by the Endocrine Society.
PY - 2016/10
Y1 - 2016/10
N2 - Context: The initiation of term and preterm labor is associated with an up-regulated inflammatory response in myometrium; however, the underlying signaling pathways remain incompletely defined. Objective: To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR). Design and Setting: Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility. Patients: Myometrial tissues from 15 term pregnant women undergoing elective cesarean section (not in labor) and 10 term pregnant women undergoing emergency cesarean section (in labor) were used. Results: Expression of the highly conserved microRNA, miR-181a, was significantly decreased in mouse and human myometrium during late gestation. By contrast, the putative miR-181a targets, TNF-β, and estrogen receptor (ER)-β, and the validated target, c-Fos, key factors in the inflammatory response leading to parturition, were coordinately up-regulated. In studies using human myometrial cells, overexpression of miR-181a mimics repressed basal as well as IL-1-induced TNF-β, C-C motif chemokine ligand 2 and 8 expression, whereas the expression of the antiinflammatory cytokine, IL-10, was increased. Overexpression of miR-181a dramatically inhibited both spontaneous and IL-1-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERβ and decreased its expression, whereas estradiol-17-reciprocally inhibited expression of mature miR-181a in myometrial cells. Conclusions: Thus, increased estradiol-17-/ERβ signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERβ and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences.
AB - Context: The initiation of term and preterm labor is associated with an up-regulated inflammatory response in myometrium; however, the underlying signaling pathways remain incompletely defined. Objective: To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR). Design and Setting: Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility. Patients: Myometrial tissues from 15 term pregnant women undergoing elective cesarean section (not in labor) and 10 term pregnant women undergoing emergency cesarean section (in labor) were used. Results: Expression of the highly conserved microRNA, miR-181a, was significantly decreased in mouse and human myometrium during late gestation. By contrast, the putative miR-181a targets, TNF-β, and estrogen receptor (ER)-β, and the validated target, c-Fos, key factors in the inflammatory response leading to parturition, were coordinately up-regulated. In studies using human myometrial cells, overexpression of miR-181a mimics repressed basal as well as IL-1-induced TNF-β, C-C motif chemokine ligand 2 and 8 expression, whereas the expression of the antiinflammatory cytokine, IL-10, was increased. Overexpression of miR-181a dramatically inhibited both spontaneous and IL-1-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERβ and decreased its expression, whereas estradiol-17-reciprocally inhibited expression of mature miR-181a in myometrial cells. Conclusions: Thus, increased estradiol-17-/ERβ signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERβ and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences.
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U2 - 10.1210/jc.2016-2078
DO - 10.1210/jc.2016-2078
M3 - Article
C2 - 27459534
AN - SCOPUS:84991728633
SN - 0021-972X
VL - 101
SP - 3646
EP - 3656
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 10
ER -