Visfatin regulates the terminal processes of human labour and delivery via activation of the nuclear factor-κB pathway

Abstract

The inflammatory process plays a pivotal role during the pathogenesis of human labour, both at term and preterm. Visfatin levels increase during normal human pregnancy and in infection associated preterm labour. The effects of visfatin in the processes of human labour and delivery, however, are not known. The aim of this study was to determine the effect of visfatin on the 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 50 ng/ml visfatin for 24 h ( n = 6). Inflammatory gene expression was analysed by quantitative RT-PCR (qRT-PCR), the medium was collected and cytokine, prostaglandin and 8-isoprostane (marker of oxidative stress) release was quantified by ELISA, and secretory protease activity by zymography. Visfatin significantly increased IL-6 and IL-8 gene expression and secretion, COX-2 expression and resultant prostaglandin (PG) E 2 and PGF 2α release, and 8-isoprostane release. There was, however, no effect of visfatin on pro MMP-9 enzyme activity. These actions of visfatin were elicited via the nuclear factor-κB (NF-κB) pathway as visfatin induced the degradation of IκB-α (inhibitor of NF-κB) whilst increasing NF-κB p65 DNA binding activity. Further to this, visfatin-induced pro-labour responses were abrogated by treatment with the NF-κB inhibitor BAY 11-7082. Collectively, these data indicate that visfatin activates pro-inflammatory cytokine release and phospholipid metabolism in human placenta via activation of the NF-κB pathway. Thus, visfatin represents a novel cytokine linked to the events of human labour initiation.