title: HoxA13 Stimulates Myometrial Cells to Secrete IL-1β and Enhance the Expression of Contraction-Associated Proteins.
abstract: Bipedalism in humans requires regionalization of myometrial function with a contracted lower uterine segment and a relaxed fundus during pregnancy to prevent fetal pressure on the cervix and reversal of this phenotype during labor. The HoxA13 gene is highly expressed in the lower uterine segment before term labor and regulates the regionalization of myometrium contractility. However, how HoxA13 regulates signal pathways to exert its functions remains unclear. Using a gene microarray technique, we profiled HoxA13 transcriptome in myometrial cells containing immune response genes (eg, IL-1β, IL-6, and IL-8) and contraction-associated proteins (CAPs) such as cyclooxygenase-2 (Cox-2) and connexin-43. IL-1β is responsible for mediating HoxA13 actions in up-regulating IL-6, IL-8, Cox-2, and connexin-43 expression. Blocking IL-1β with its inhibitor abolishes these HoxA13 actions. HoxA13-induced IL-1β stimulates the recruitment of activated THP-1 monocytes to myometrial cells, which in turn amplify the secretion of IL-1β, IL-6, and IL-8 through a mutual feed-forward loop between these cell types. As a result, Cox-2 expression is dramatically enhanced. These findings lead us to conclude that HoxA13 increases myometrial cell contractility by enhancing the secretion of IL-1β, resulting in an up-regulation of CAP and other proinflammatory cytokine expression. HoxA13-induced IL-1β in myometrial cells also prompts leukocyte recruitment and further amplifies CAP expression.
authors.affiliation: Vancouver Prostate Centre (H.L., Y.Y., Y.S., L.F., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver, Canada V6H 3Z6; Department of Physiology and Pharmacology (D.S.), University of Calgary, Calgary, Canada T2N 4N1; and Department of Obstetrics and Gynaecology (S.L., X.D.), University of Toronto, Toronto, Canada M5G 1E2.
authors.forename: Haolong
authors.initials: H
authors.lastname: Li
authors.affiliation: Vancouver Prostate Centre (H.L., Y.Y., Y.S., L.F., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver, Canada V6H 3Z6; Department of Physiology and Pharmacology (D.S.), University of Calgary, Calgary, Canada T2N 4N1; and Department of Obstetrics and Gynaecology (S.L., X.D.), University of Toronto, Toronto, Canada M5G 1E2.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Vancouver Prostate Centre (H.L., Y.Y., Y.S., L.F., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver, Canada V6H 3Z6; Department of Physiology and Pharmacology (D.S.), University of Calgary, Calgary, Canada T2N 4N1; and Department of Obstetrics and Gynaecology (S.L., X.D.), University of Toronto, Toronto, Canada M5G 1E2.
authors.forename: Yao
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Vancouver Prostate Centre (H.L., Y.Y., Y.S., L.F., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver, Canada V6H 3Z6; Department of Physiology and Pharmacology (D.S.), University of Calgary, Calgary, Canada T2N 4N1; and Department of Obstetrics and Gynaecology (S.L., X.D.), University of Toronto, Toronto, Canada M5G 1E2.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Vancouver Prostate Centre (H.L., Y.Y., Y.S., L.F., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver, Canada V6H 3Z6; Department of Physiology and Pharmacology (D.S.), University of Calgary, Calgary, Canada T2N 4N1; and Department of Obstetrics and Gynaecology (S.L., X.D.), University of Toronto, Toronto, Canada M5G 1E2.
authors.forename: Donna
authors.initials: D
authors.lastname: Slater
authors.affiliation: Vancouver Prostate Centre (H.L., Y.Y., Y.S., L.F., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver, Canada V6H 3Z6; Department of Physiology and Pharmacology (D.S.), University of Calgary, Calgary, Canada T2N 4N1; and Department of Obstetrics and Gynaecology (S.L., X.D.), University of Toronto, Toronto, Canada M5G 1E2.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lye
authors.affiliation: Vancouver Prostate Centre (H.L., Y.Y., Y.S., L.F., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver, Canada V6H 3Z6; Department of Physiology and Pharmacology (D.S.), University of Calgary, Calgary, Canada T2N 4N1; and Department of Obstetrics and Gynaecology (S.L., X.D.), University of Toronto, Toronto, Canada M5G 1E2.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Dong
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009215:Myometrium / Q000378:metabolism*; D034622:RNA Interference; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D018031:Connexin 43; D018398:Homeodomain Proteins; D053583:Interleukin-1beta; C099959:homeobox protein HOXA13; D051546:Cyclooxygenase 2