Nuclear factor-κB mediates placental growth factor induced pro-labour mediators in human placenta.
Prostaglandins, pro-inflammatory cytokines, extracellular matrix remodelling enzymes and nuclear factor-kappa B (NF-κB) are involved in the mechanisms of term and preterm parturition. Recent studies have reported an increase in angiogenesis-related genes during term and preterm labour, including placental growth factor (PLGF). In non-gestational tissues, PLGF induces inflammation via NF-κB. The aim of this study was to determine the effect of PLGF on the gene expression and release of pro-labour mediators in human placenta. Samples were obtained from normal pregnancies at the time of Caesarean section. Human placenta was incubated in the absence (basal control) or presence of a 10 ng/ml PLGF for 24 h. Inflammatory gene expression was analysed by quantitative RT-PCR, concentration of pro-inflammatory cytokines and prostaglandins was quantified by ELISA, and secretory matrix metalloproteinases (MMPs) activity by zymography. NF-κB DNA-binding activity and IκB-α (inhibitor of NF-κB) protein degradation were analysed by ELISA and Western blotting, respectively. PLGF significantly increased interleukin (IL)-6 and IL-8 gene expression and secretion, cyclooxygenase-2 expression and resultant prostaglandin (PG) E(2) and PGF(2α) release, and MMP-9 gene expression and enzyme production. PLGF induced the degradation of IκB-α whilst increasing NF-κB p65 DNA-binding activity. The PLGF-induced pro-labour responses were abrogated by co-treatment with the NF-κB inhibitor BAY 11-7082. In summary, the pro-inflammatory and pro-labour effects of PLGF in human placenta are mediated by NF-κB.
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, VIC 3084, Australia. mlappas@unimelb.edu.au
Martha
M
Lappas
D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D015237:Dinoprost; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone