The transcription factor Nrf2 is decreased after spontaneous term labour in human fetal membranes where it exerts anti-inflammatory properties

Introduction: Inflammation plays a central role in the terminal processes of human labour and delivery, including the rupture of fetal membranes. Recent studies show a role for the transcription factor Nrf2 (NF-E2-related factor 2) in regulating inflammation. The aims of this study were to determine the effect of human spontaneous term and preterm labour on Nrf2 expression in fetal membranes; and Nrf2 siRNA knockdown on pro-inflammatory cytokines.

Methods: Fetal membranes, from term and preterm, were obtained from non-labouring and labouring women. Primary amnion cells were used to determine the effect of Nrf2 siRNA knockdown on pro-inflammatory cytokines in the presence of inflammation or infection.

Results: Nrf2 mRNA expression and nuclear protein expression were significantly decreased after spontaneous term labour and delivery. There was, however, no effect of spontaneous preterm labour and delivery on Nrf2 mRNA expression and nuclear protein expression. On the other hand, Nrf2 gene expression was significantly lower in fetal membranes obtained from women at preterm with histologic chorioamnionitis compared to fetal membranes obtained from women at preterm without histologic chorioamnionitis. Nrf2 silencing by siRNA in primary amnion cells was associated with a significant increase in IL-6 and IL-8 mRNA expression and release induced by IL-1β, TNF-α, flagellin and poly(I:C).

Discussion: Nrf2 has an anti-inflammatory effect in human fetal membranes. It is decreased with term labour and preterm chorioamnionitis; and Nrf2 silencing increases inflammation- and infection-induced pro-inflammatory cytokines. Further studies are required to determine if agents that can increase Nrf2 expression may be a potential therapeutic strategy in the treatment and management of infection-induced preterm labour.