Interleukin-1 Receptor Accessory Protein Amplifies Trophoblast Inflammatory Signaling in Inflammation-Associated Preterm Birth.

PROBLEM: Inflammation contributes to spontaneous preterm birth, yet mechanisms regulating trophoblast inflammatory responsiveness remain unclear. Interleukin-1 beta (IL1β) is a potent mediator of labor-associated inflammation, but the role of its accessory receptor, IL-1 receptor accessory protein (IL-1RAP), at the maternal-fetal interface is poorly understood. METHOD OF STUDY: IL-1RAP expression and localization were assessed in preterm chorioamniotic membranes with or without intra-amniotic inflammation. Decidual regulation of trophoblast IL1RAP was evaluated in primary trophoblasts, and gain- and loss-of-function studies in HTR8/SVneo cells tested its role in IL-1β-induced inflammatory signaling. RESULTS: IL1RAP expression was increased in fetal membranes from inflammation-associated preterm labor and IL-1RAP localized prominently to extravillous trophoblasts. Decidual cell-conditioned media increased trophoblast IL1RAP expression. IL1RAP overexpression enhanced basal and IL-1β-induced expression of inflammatory mediators, including TNF, IL1B, IL6, and CXCL8/IL8, whereas IL1RAP silencing most consistently attenuated IL-1β-induced TNF expression. CONCLUSIONS: These findings identify trophoblast IL-1RAP as an amplifier of IL-1β-mediated inflammatory signaling and support further investigation of IL-1RAP in inflammation-associated preterm birth.