Corticotropin-Releasing Hormone (CRH) Promotes Inflammation in Human Pregnant Myometrium: The Evidence of CRH Initiating Parturition?

Context: An increasing body of evidence indicates that human labor, either term or preterm, is an inflammatory event. CRH has been implicated to be a trigger of human parturition. Objective: To investigate whether CRH induces the cascades of inflammation in human pregnant myometrium, thereby leading to activation of uterus. Design: The myometrial tissues were obtained from pregnant women who were in labor or not in labor at term. The output of cytokines and prostaglandins (PGs) was determined by Multiplex and ELISA. Western blot analysis was used to determine the levels of uterine activation proteins (UAPs). Results: The levels of chemokines and cytokines as well as activated nuclear factor-kappa B (NF-kappa B) were increased in the term labor group more than the not term labor group. CRH stimulated production of a number of chemokines and cytokines in cultured uterine smooth muscle cells (USMCs), which induced chemotaxis of monocytes. These effects were mediated by CRH receptor 1 (CRHR1) and dependent on adenylyl cyclase/protein kinase (PKA) and NF-kappa B signaling. Cocultures of CRH-treated USMCs with monocytes greatly enhanced the output of cytokines and chemokines as well as PGs in cultures and increased the expression of uterine activation proteins (UAPs) in USMCs. IL-1 beta, IL-6, and TNF-alpha stimulated the expression of UAPs and output of PGs in USMCs. Conclusions: CRH induces the production of chemokines and cytokines in myometrium at term and subsequently results in the cascade of inflammation in uterus. The inflammation induced by CRH can lead to activation of uterus.