Autophagy, which is decreased in labouring fetal membranes, regulates IL-1β production via the inflammasome

Abstract

IntroductionIL-1β plays a vital role in the terminal processes of human labour and delivery. Inflammasome activation is required to process pro IL-1β to an active, secreted molecule. Recent studies have shown that autophagy regulates IL-1β via the inflammasome. The aims were to determine the effect of (i) human spontaneous term and preterm labour on the expression of autophagy proteins in fetal membranes; and (ii) autophagy inhibition on IL-1β release. MethodsFetal membranes, from term and preterm, were obtained from non-labouring and labouring women. Tissue explants were used to determine the effect of inhibition of autophagy on IL-1β secretion. ResultsExpression of the autophagy proteins Beclin-1, Atg3, Atg5, Atg7, Atg12, Atg16L1 were lower after spontaneous term labour. Beclin-1 and Atg7 expression were lower after spontaneous preterm labour. Beclin-1, Atg3, and Atg7 expression were lower after preterm pre-labour rupture of membranes (PPROM) compared to preterm with intact membranes. LC3B-I expression was higher after spontaneous term and preterm labour and with PPROM; there was no difference in LC3B-II expression between the two groups. The autophagy inhibitor LY290042 increased IL-1β secretion in the presence of bacterial endotoxin LPS; IL-1β secretion was ameliorated in the presence inflammasome inhibitors. DiscussionAutophagy is decreased in fetal membranes after spontaneous labour and delivery, and PPROM. Inhibition of autophagy regulates the secretion of IL-1β via inflammasome activation. IL-1β is a major contributor to the pathophysiology of spontaneous preterm birth. Therefore activation of autophagy may be a potential therapeutic mechanism to delay or prevent infection-induced preterm birth.