Membrane progesterone receptor alpha: implications for human and mouse preterm labor (795.2)

Abstract

Functional progesterone (P4) withdrawal leading to labor is achieved in part by regulation of the ratio of nuclear progesterone receptor (PR) A to B. The role of membrane‐associated PR (mPR) in pregnancy and labor is not clear. We observed that human placental expression of mPRα mRNA, but not COX2, IL‐1β and oxytocin receptor (OXTR), rises with increasing gestational age at labor. In a mouse model, intrauterine injection of either E. coli or peptidoglycan + polyinosinic: polycytidylic acid on gestational day 15 significantly decreased expression of mPRα in uterus but not in placenta harvested eight hours after injection, and increased expression of COX2 in both uterus and placenta. In a murine macrophage cell line (RAW264.7), activation of mPRs by P4 modified to be active only extracellularly by conjugation to BSA (P4‐BSA, 100 nM) caused a pro‐inflammatory shift in mRNA expression profile, with significant down‐regulation of mPRα and OXTR and up‐regulation of the expression of COX2, IL‐1β, and TNF. Pretreatment with PD98059, a MEK 1/2 inhibitor significantly reduced P4‐BSA‐induced IL‐1β, TNF and COX‐2 mRNA. Inhibition of PKA by H89 blocked P4‐BSA‐induced IL‐1β and TNF mRNA levels. These data suggest that MEK1/2 and PKA activities are involved in the signaling of mPRs. Taken together, we demonstrated that change in mPRα expression and signaling are associated with the inflammatory responses in labor.Grant Funding Source: R01HD41689