title: Oxytocin activates NF-κB-mediated inflammatory pathways in human gestational tissues.
abstract: Human labour, both at term and preterm, is preceded by NF-κB-mediated inflammatory activation within the uterus, leading to myometrial activation, fetal membrane remodelling and cervical ripening. The stimuli triggering inflammatory activation in normal human parturition are not fully understood. We show that the neurohypophyseal peptide, oxytocin (OT), activates NF-κB and stimulates downstream inflammatory pathways in human gestational tissues. OT stimulation (1 pM-100 nM) specifically via its receptor (OTR) in human myometrial and amnion primary cells led to MAPK and NF-κB activation within 15 min and maximal p65-subunit nuclear translocation within 30 min. Both in human myometrium and amnion, OT-induced activation of the canonical NF-κB pathway upregulated key inflammatory labour-associated genes including IL-8, CCL5, IL-6 and COX-2. IKKβ inhibition (TPCA1; 10 µM) suppressed OT-induced NF-κB-p65 phosphorylation, whereas p65-siRNA knockdown reduced basal and OT-induced COX-2 levels in myometrium and amnion. In both gestational tissues, MEK1/2 (U0126; 10 µM) or p38 inhibition (SB203580; 10 µM) suppressed OT-induced COX-2 expression, but OT-induced p65-phosphorylation was only inhibited in amnion, suggesting OT activation of NF-κB in amnion is MAPK-dependent. Our data provide new insight into the OT/OTR system in human parturition and suggest that its therapeutic modulation could be a strategy for regulating both contractile and inflammatory pathways in the clinical context of term/preterm labour.
authors.affiliation: Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, United Kingdom.
authors.forename: Sung Hye
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: MacIntyre
authors.affiliation: Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Firmino Da Silva
authors.affiliation: University of Warwick, Clinical Sciences Research Institute, Warwick Medical School, UHCW, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blanks
authors.affiliation: Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, United Kingdom.
authors.forename: Yun S
authors.initials: YS
authors.lastname: Lee
authors.affiliation: University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Thornton
authors.affiliation: Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, United Kingdom.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Bennett
authors.affiliation: Imperial College London, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 0NN, United Kingdom; Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom. Electronic address: v.terzidou@imperial.ac.uk.
authors.forename: Vasso
authors.initials: V
authors.lastname: Terzidou
mesh_terms: D000328:Adult; D000650:Amnion / Q000166:cytology / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D009215:Myometrium / Q000166:cytology / Q000378:metabolism*; D010121:Oxytocin / Q000235:genetics / Q000378:metabolism*; D036801:Parturition / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D061251:Primary Cell Culture; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C569600:OXTR protein, human; D018045:Receptors, Oxytocin; D051996:Transcription Factor RelA; D010121:Oxytocin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C482128:MAP2K2 protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: Amnion; Inflammation; Myometrium; NF-κB; Oxytocin; Parturition