Corticotrophin‐releasing hormone up regulated IL‐6, IL‐8 and MCP‐1 output in primary human myometrial smooth muscle cells via CRHR1 by activating the PKA pathway

Abstract

CRH has been implicated to be involved in controlling the length of pregnancy and initiating the onset of parturition in human. Given that parturition is an inflammatory process, we hypothesized that CRH regulates the inflammation responses by controlling the production of cytokines and chemokines in human myometrium, thereby leading to parturition. Primary myometrial cells were isolated and cultured from lower segmental myometrial tissues obtained from pregnant women at term. CRH treatment caused an increase in IL‐6, IL‐8 and MCP‐1 production in myometrial cells. These effects were reversed by CRHR1 antagonist but not by CRHR2 antagonist. Knockdown of CRHR1 resulted in a loss of CRH effect. CRH stimulated active Gαs protein and resulted in an increase in cAMP production in myometrial cells. CRH‐induced production of IL‐6, IL‐8 and MCP‐1 was blocked by either adenylate cyclase (AC) inhibitor SQ22536 or PKA inhibitor H89. In conclusion, CRH acts on CRHR1 to stimulate the production of cytokine and chemokine in myometrial cells. These effects are dependent on AC/PKA signaling pathway. Our data suggest that CRH can directly stimulate myometrial cells to secret chemokines and cytokines, which could recruit leukocytes to the uterus and activation of inflammation response.