Role of IRG1 in Regulating Pro-inflammatory and Pro-labor Mediators in Human Myometrium.

Preterm birth is a major contributor to neonatal deaths and associated long-term morbidities for the survivors, yet therapies remain elusive, given our incomplete understanding of the mechanisms driving human labor and delivery. Human labor is an inflammatory process, and we investigated whether IRG1 (immunoresponsive gene-1) plays a role in these processes. We demonstrate that IRG1 mRNA and protein expression is significantly increased in myometrium with human term labor, compared to no labor samples, and with preterm (LPS) labor in a mouse model. Pro-labor mediators such as pro-inflammatory cytokines TNF and IL1B, and TLR ligands fsl-1, flagellin, LPS, and poly(I:C) also increased IRG1 mRNA expression in myometrial explants. IRG1 silencing, using siRNA in primary myometrial cells, displayed a decrease in the expression of inflammation-induced pro-inflammatory cytokines (IL1A, IL6), chemokines (CCL2, CXCL1, CXCL8), adhesion molecules (ICAM1, VCAM1), and contractility (PTGFR mRNA expression, prostaglandin F2α release, and in situ gel contraction assay). Our results suggest that IRG1 is involved when pro-labor mediators activate the inflammatory processes of human labor, warranting further investigation.