COX-1/PGE2/EP4 alleviates mucosal injury by upregulating \u03b2-arr1-mediated Akt signaling in colitis

Xiaojie Peng,Bin Wu,Jin Tao,Jie Jiang,Siwei Tan,Jianzhong Li,Minyi Xu,Huiling Liu

doi:10.1038/s41598-017-01169-6

Xiaojie Peng, Bin Wu + Show 6 more

Open Access

https://doi.org/10.1038/s41598-017-01169-6

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Abstract

COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC). β-arrestin1 (β-arr1), which acts as a scaffold protein, is involved in PGE2-mediated signaling pathways. However, the interaction between PGE2 and β-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, β-arr1 deficient mice showed increased signs of colitis compared to β-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in β-arr1 deficient mice. In parallel, HCT116 cells transfected with β-arr1 siRNA were examined in the presence or absence of PGE2in vitro. PGE2 treatment in the β-arr1 WT/KO DSS model and β-arr1 siRNA transfection of HCT116 cells confirmed that PGE2 upregulated β-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE2/EP4 upregulates the β-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.

Highlights

Inflammatory bowel disease (IBD), a multifactorial disease perpetuated by a dysregulated immune response, includes ulcerative colitis and Crohn’s disease
We demonstrated that PGE2 treatment alleviated mucosal injury in colitis
We revealed the role of EP4 receptors and PGE2-induced β-arr1/p-Akt signaling in maintaining epithelial barrier integrity

Summary

Introduction

Inflammatory bowel disease (IBD), a multifactorial disease perpetuated by a dysregulated immune response, includes ulcerative colitis and Crohn’s disease. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are occasionally involved in the development of de novo colitis, they are more frequently implicated in the aggravation of pre-existing intestinal diseases[3]. To the development of experimental colitis and mucosal repair in the process of UC18, 19 In addition to their role in receptor downregulation, β-arrs act as scaffold proteins to accelerate signal transduction in the EP4 pathway. PGE2 contributed to the preservation of epithelial proliferation of experimental colitis by mainly enhancing EP4/β-arr1/p-Akt signaling. Taken together, these findings demonstrated the pivotal role of β-arr[1] in the integrity of the PGE2-mediated colonic epithelial barrier and provided sufficient scientific evidence to establish EP4/β-arr1/p-Akt signaling as a new therapeutic target of UC

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