Lu Gao1, Gang Wang1, Wei-Na Liu1, Holly Kinser1, Hector L Franco1, Carole R Mendelson1. 1. 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.
Abstract
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-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. CONCLUSIONS: 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.
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-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. CONCLUSIONS: 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: Jason S Carroll; Clifford A Meyer; Jun Song; Wei Li; Timothy R Geistlinger; Jérôme Eeckhoute; Alexander S Brodsky; Erika Krasnickas Keeton; Kirsten C Fertuck; Giles F Hall; Qianben Wang; Stefan Bekiranov; Victor Sementchenko; Edward A Fox; Pamela A Silver; Thomas R Gingeras; X Shirley Liu; Myles Brown Journal: Nat Genet Date: 2006-10-01 Impact factor: 38.330
Authors: Emmette R Hutchison; Elisa M Kawamoto; Dennis D Taub; Ashish Lal; Kotb Abdelmohsen; Yongqing Zhang; William H Wood; Elin Lehrmann; Simonetta Camandola; Kevin G Becker; Myriam Gorospe; Mark P Mattson Journal: Glia Date: 2013-05-07 Impact factor: 7.452
Authors: Dawn R Cochrane; Diana M Cittelly; Erin N Howe; Nicole S Spoelstra; Erin L McKinsey; Kelly LaPara; Anthony Elias; Douglas Yee; Jennifer K Richer Journal: Horm Cancer Date: 2010-12 Impact factor: 3.869
Authors: Frank Cichocki; Martin Felices; Valarie McCullar; Steven R Presnell; Ahmad Al-Attar; Charles T Lutz; Jeffrey S Miller Journal: J Immunol Date: 2011-11-14 Impact factor: 5.422
Authors: Hannah H Chang; Jim Larson; Hannah Blencowe; Catherine Y Spong; Christopher P Howson; Sarah Cairns-Smith; Eve M Lackritz; Shoo K Lee; Elizabeth Mason; Andrew C Serazin; Salimah Walani; Joe Leigh Simpson; Joy E Lawn Journal: Lancet Date: 2012-11-16 Impact factor: 79.321
Authors: Sam Mesiano; Eng-Cheng Chan; John T Fitter; Kenneth Kwek; George Yeo; Roger Smith Journal: J Clin Endocrinol Metab Date: 2002-06 Impact factor: 5.958
Authors: Li Liu; Hope L Johnson; Simon Cousens; Jamie Perin; Susana Scott; Joy E Lawn; Igor Rudan; Harry Campbell; Richard Cibulskis; Mengying Li; Colin Mathers; Robert E Black Journal: Lancet Date: 2012-05-11 Impact factor: 79.321
Authors: Pablo Landgraf; Mirabela Rusu; Robert Sheridan; Alain Sewer; Nicola Iovino; Alexei Aravin; Sébastien Pfeffer; Amanda Rice; Alice O Kamphorst; Markus Landthaler; Carolina Lin; Nicholas D Socci; Leandro Hermida; Valerio Fulci; Sabina Chiaretti; Robin Foà; Julia Schliwka; Uta Fuchs; Astrid Novosel; Roman-Ulrich Müller; Bernhard Schermer; Ute Bissels; Jason Inman; Quang Phan; Minchen Chien; David B Weir; Ruchi Choksi; Gabriella De Vita; Daniela Frezzetti; Hans-Ingo Trompeter; Veit Hornung; Grace Teng; Gunther Hartmann; Miklos Palkovits; Roberto Di Lauro; Peter Wernet; Giuseppe Macino; Charles E Rogler; James W Nagle; Jingyue Ju; F Nina Papavasiliou; Thomas Benzing; Peter Lichter; Wayne Tam; Michael J Brownstein; Andreas Bosio; Arndt Borkhardt; James J Russo; Chris Sander; Mihaela Zavolan; Thomas Tuschl Journal: Cell Date: 2007-06-29 Impact factor: 41.582
Authors: Chinwendu Amazu; Xiaofeng Ma; Clara Henkes; Juan J Ferreira; Celia M Santi; Sarah K England Journal: Am J Physiol Endocrinol Metab Date: 2020-01-14 Impact factor: 4.310