title: Inhibition of lysyl oxidase by prostaglandin E2 via EP2/EP4 receptors in human amnion fibroblasts: Implications for parturition.
abstract: The underlying mechanism leading to rupture of the membranes at parturition is not fully understood. Lysyl oxidase (LOX) cross-links collagen fibrils thereby increasing the tensile strength of the membranes. Thus, understanding the regulation of LOX expression may be of crucial importance for elucidation of the process of rupture of the fetal membranes. Prostaglandin E2 (PGE2), mainly produced in the amnion, plays crucial roles during human parturition. However it is not known whether PGE2 regulates LOX expression in the fetal membranes. Using primary human amnion fibroblasts, we showed that addition of PGE2 decreased LOX mRNA and protein levels, which were blocked by inhibition of EP2/EP4 receptors and the receptor-coupled cAMP/PKA pathway. EP2/EP4 receptor agonists and stimulators of the cAMP/PKA pathway consistently decreased LOX expression. Furthermore, PGE2 induced cyclo-oxygenase-2 (COX-2) expression, a key enzyme in PGE2 production, via an EP2 and EP4 receptor-coupled cAMP/PKA pathway. Small interfering RNA-mediated knock-down of COX-2 expression significantly increased the basal expression of LOX. In addition, an increase in COX-2 and a reciprocal decrease in LOX abundance occurred in amnion tissue following labor at term. In conclusion, we have revealed a feed-forward loop of induction of COX-2 and reduction in LOX expression by PGE2 acting via an EP2/EP4 receptor-coupled cAMP/PKA pathway in human amnion fibroblasts toward the end of gestation, which may play a significant role in the rupture of fetal membranes.
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, No.401 Hospital, Qingdao, Shandong, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China.
authors.forename: Wangsheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Changning Maternity and Infant Health Hospital, Shanghai, PR China; Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China.
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.affiliation: Changning Maternity and Infant Health Hospital, Shanghai, PR China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Shu
authors.affiliation: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China.
authors.forename: Zi-Jiang
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Myatt
authors.affiliation: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, PR China. Electronic address: sungangrenji@hotmail.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D000650:Amnion / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D036801:Parturition / Q000378:metabolism; D011247:Pregnancy; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000594:Amino Acid Oxidoreductases; D015232:Dinoprostone
keywords: Amnion; Cyclooxygenase-2; Lysyl oxidase; Parturition; Prostaglandin E2