COX-1/PGE₂/EP4 alleviates mucosal injury by upregulating ?-arr1-mediated Akt signaling in colitis.

ABSTRACT: COX-1/PGE₂ is an important protective mediator in ulcerative colitis (UC). ?-arrestin1 (?-arr1), which acts as a scaffold protein, is involved in PGE₂-mediated signaling pathways. However, the interaction between PGE₂ and ?-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE₂ were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. PGE₂ treatment was found to alleviate mucosal injury and induce EP4 expression during dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) mice. Following DSS-induced injury, ?-arr1 deficient mice showed increased signs of colitis compared to ?-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in ?-arr1 deficient mice. In parallel, HCT116 cells transfected with ?-arr1 siRNA were examined in the presence or absence of PGE₂ in vitro. PGE₂ treatment in the ?-arr1 WT/KO DSS model and ?-arr1 siRNA transfection of HCT116 cells confirmed that PGE₂ upregulated ?-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE₂/EP4 upregulates the ?-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis. Thus, these findings provide support for the future development and clinical application of COX-1/PGE₂ in UC.

SUBMITTER: Peng X 

PROVIDER: S-EPMC5430694 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature