title: The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(αi) signalling.
abstract: Oxytocin (OT) plays an important role in the onset of human labour by stimulating uterine contractions and promoting prostaglandin/inflammatory cytokine synthesis in amnion via oxytocin receptor (OTR) coupling. The OTR-antagonist, Atosiban, is widely used as a tocolytic for the management of acute preterm labour. We found that in primary human amniocytes, Atosiban (10 μM) signals via PTX-sensitive Gαi to activate transcription factor NF-κB p65, ERK1/2, and p38 which subsequently drives upregulation of the prostaglandin synthesis enzymes, COX-2 and phospho-cPLA2 and excretion of prostaglandins (PGE2) (n = 6; p < 0.05, ANOVA). Moreover, Atosiban treatment increased expression and excretion of the inflammatory cytokines, IL-6 and CCL5. We also showed that OT-simulated activation of NF-κB, ERK1/2, and p38 and subsequent prostaglandin and inflammatory cytokine synthesis is via Gαi-2 and Gαi-3 but not Gαq, and is not inhibited by Atosiban. Activation or exacerbation of inflammation is not a desirable effect of tocolytics. Therefore therapeutic modulation of the OT/OTR system for clinical management of term/preterm labour should consider the effects of differential G-protein coupling of the OTR and the role of OT or selective OTR agonists/antagonists in activating proinflammatory pathways.
authors.affiliation: Imperial College London, Institute of Reproductive and Developmental Biology, Dept. Surgery and Cancer, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, UK.
authors.forename: Sung Hye
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Imperial College London, Institute of Reproductive and Developmental Biology, Dept. Surgery and Cancer, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: MacIntyre
authors.affiliation: Imperial College London, Institute of Reproductive and Developmental Biology, Dept. Surgery and Cancer, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, UK.
authors.forename: Aylin C
authors.initials: AC
authors.lastname: Hanyaloglu
authors.affiliation: University of Warwick, Clinical Sciences Research Institute, Warwick Medical School, UHCW, Clifford Bridge Road, Coventry CV2 2DX, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blanks
authors.affiliation: The University of Exeter Medical School, Main Medical School Building, St Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Thornton
authors.affiliation: Imperial College London, Institute of Reproductive and Developmental Biology, Dept. Surgery and Cancer, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, UK.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Bennett
authors.affiliation: Imperial College London, Institute of Reproductive and Developmental Biology, Dept. Surgery and Cancer, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, UK; Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK. Electronic address: v.terzidou@imperial.ac.uk.
authors.forename: Vasso
authors.initials: V
authors.lastname: Terzidou
mesh_terms: D000650:Amnion / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010121:Oxytocin / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D054467:Phospholipases A2 / Q000378:metabolism; D011247:Pregnancy; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014668:Vasotocin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D047630:Depsipeptides; C000607068:FR900359; D018836:Inflammation Mediators; D016328:NF-kappa B; D018045:Receptors, Oxytocin; C047046:atosiban; D010121:Oxytocin; D051546:Cyclooxygenase 2; D037342:Pertussis Toxin; D054467:Phospholipases A2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D014668:Vasotocin
keywords: Amnion; G protein; NF-κB; Oxytocin; Parturition