title: Inhibition of Lysyl Oxidase by Cortisol Regeneration in Human Amnion: Implications for Rupture of Fetal Membranes.
abstract: The mechanisms underlying human parturition are still not understood, yet we need this knowledge to combat preterm birth. Fetal membranes express abundant 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which converts inert cortisone to active cortisol. We examined whether cortisol regeneration in the amnion might play a role in human parturition through regulation of lysyl oxidase (LOX), a collagen cross-linking enzyme, thereby contributing to the rupture of fetal membranes. By using cultured human primary amnion fibroblasts, we demonstrated that, in addition to the induction of the key enzymes involved in prostaglandin E2 (PGE2) synthesis, cortisol stimulated 11β-HSD1 and inhibited LOX reciprocally. These results were reproduced in human amnion tissue explants after cortisol treatment. Cortisone also inhibited LOX expression, which was abolished by the inhibition of 11β-HSD1. Despite the inhibition of LOX by PGE2, inhibition of the PGE2 pathway failed to block the inhibition of LOX by cortisol. However, inhibition of glucocorticoid receptor and mutation of a negative glucocorticoid response element in LOX promoter abolished the inhibition of LOX by cortisol. Chromatin immunoprecipitation assay revealed that cortisol increased GR binding to the LOX promoter. Moreover, increased cortisol and 11β-HSD1 abundance and decreased LOX abundance were observed in human amnion tissue after the labor-initiated spontaneous rupture of membranes. These data highlight a crucial role for local cortisol regeneration by 11β-HSD1 in the down-regulation of LOX expression via glucocorticoid receptor binding to a negative glucocorticoid response element to its promoter in the amnion, which may contribute to rupture of fetal membranes at parturition.
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Chunming
authors.initials: C
authors.lastname: Guo
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Wangsheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Leslie
authors.initials: L
authors.lastname: Myatt
authors.affiliation: Center for Reproductive Medicine (W.W., W.L., Y.M., K.S.), Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (W.W., W.L., Y.M., K.S.), Shanghai 200135, People's Republic of China; School of Life Sciences (C.L., C.G.), Fudan University, Shanghai 200433, People's Republic of China; Department of Obstetrics and Gynecology (P.Z.), Number 401 Hospital, Qingdao 266100, People's Republic of China; and Department of Obstetrics and Gynecology (L.M.), Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000650:Amnion / Q000201:enzymology*; D003348:Cortisone; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D036801:Parturition / Q000378:metabolism*; D011247:Pregnancy; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D011965:Receptors, Glucocorticoid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D008249:Protein-Lysine 6-Oxidase; D015232:Dinoprostone; D003348:Cortisone; D006854:Hydrocortisone