Oxytocin activates NF-κB-mediated inflammatory pathways in human gestational tissues

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:403

Article

Kim, Sung Hye¹  MacIntyre, David A.¹  Da Silva, Maria Firmino¹  Blanks, Andrew M.²  Lee, Yun S.¹  Thornton, Steven³  Bennett, Phillip R.¹  Terzidou, Vasso^1,4 

[1] Univ London Imperial Coll Sci Technol & Med, Inst Reprod & Dev Biol, Parturit Res Grp, London W12 0NN, England

[2] Univ Warwick, Clin Sci Res Inst, Warwick Med Sch, UHCW, Coventry CV2 2DX, W Midlands, England

[3] Univ Exeter, Sch Med, Exeter EX2 5DW, Devon, England

[4] Univ London Imperial Coll Sci Technol & Med, Sch Med, Acad Dept Obstet & Gynaecol, Chelsea & Westminster Hosp, London SW10 9NH, England

关键词: Oxytocin;    NF-kappa B;    Inflammation;    Myometrium;    Amnion;    Parturition;   

DOI  :  10.1016/j.mce.2014.11.008

来源: Elsevier

【 摘 要 】

Human labour, both at term and preterm, is preceded by NF-kappa B-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-kappa B 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-kappa B 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-kappa 3 pathway upregulated key inflammatory labour-associated genes including IL-8, CCL5, IL-6 and COX-2. IKK beta inhibition (TPCA1; 10 mu M) suppressed OT-induced NF-kappa B-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 mu M) or p38 inhibition (SB203580; 10 mu M) suppressed OT-induced COX-2 expression, but OT-induced p65-phosphorylation was only inhibited in amnion, suggesting OT activation of NF-kappa B 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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