Interleukin‐1 Receptor Accessory Protein Amplifies Trophoblast Inflammatory Signaling in Inflammation‐Associated Preterm Birth
Jasmine Edghill, Busra Cetinkaya‐Un, Jessica Lynch, Burak Un, Isabella Hetherington, Md. Abu Rahat, Marian Kacerovsky, Charles J. Lockwood, Ozlem Guzeloglu‐Kayisli, Hana Totary‐JainABSTRACT
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/SV neo 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.