title: Reciprocal Feedback Between miR-181a and E2/ERα in Myometrium Enhances Inflammation Leading to Labor.
abstract: 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.
  
  
  
  To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR).
  
  
  
  Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility.
  
  
  
  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.
  
  
  
  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-α, and estrogen receptor (ER)-α, 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-1β-induced TNF-α, 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-1β-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERα and decreased its expression, whereas estradiol-17β reciprocally inhibited expression of mature miR-181a in myometrial cells.
  
  
  
  Thus, increased estradiol-17β/ERα signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERα and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences.
authors.affiliation: Department of Physiology (L.G., G.W., W.L.), Second Military Medical University, Shanghai 200433, People's Republic of China; Department of Biochemistry (L.G., H.K., C.R.M.) and Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics and Gynecology (C.R.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Physiology (L.G., G.W., W.L.), Second Military Medical University, Shanghai 200433, People's Republic of China; Department of Biochemistry (L.G., H.K., C.R.M.) and Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics and Gynecology (C.R.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Physiology (L.G., G.W., W.L.), Second Military Medical University, Shanghai 200433, People's Republic of China; Department of Biochemistry (L.G., H.K., C.R.M.) and Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics and Gynecology (C.R.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Liu
authors.affiliation: Department of Physiology (L.G., G.W., W.L.), Second Military Medical University, Shanghai 200433, People's Republic of China; Department of Biochemistry (L.G., H.K., C.R.M.) and Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics and Gynecology (C.R.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Holly
authors.initials: H
authors.lastname: Kinser
authors.affiliation: Department of Physiology (L.G., G.W., W.L.), Second Military Medical University, Shanghai 200433, People's Republic of China; Department of Biochemistry (L.G., H.K., C.R.M.) and Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics and Gynecology (C.R.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Hector L
authors.initials: HL
authors.lastname: Franco
authors.affiliation: Department of Physiology (L.G., G.W., W.L.), Second Military Medical University, Shanghai 200433, People's Republic of China; Department of Biochemistry (L.G., H.K., C.R.M.) and Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics and Gynecology (C.R.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Carole R
authors.initials: CR
authors.lastname: Mendelson
mesh_terms: D000328:Adult; D000818:Animals; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007743:Labor, Obstetric / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009215:Myometrium / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D047628:Estrogen Receptor alpha; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D004958:Estradiol