miR-21 Negatively Regulates the PTEN-PI3K-Akt-mTOR Signaling Pathway in Crohn's Disease by Altering Immune Tolerance and Epithelial-Mesenchymal Transition.

Abstract

miR-21 is involved in the mechanisms of inflammatory bowel disease (IBD). It negatively regulates PTEN, which is an upstream regulatory gene of the PI3K/Akt/mTOR signaling pathway. But the relationship between miR-21 and immune tolerance and intestinal epithelial injury, and the mechanism by which miR-21 participates in Crohn's disease (CD) have not been studied. We aimed to address these two questions. The results of the present study showed that the levels of miR-21 and PTEN respectively decreased and increased significantly in the intestinal mucosa from active CD compared with control ones. Transfection with miR-21-5p mimics significantly downregulated the expression of PTEN and upregulated PI3K-Akt-mTOR signaling and the downstream pathway in PBMCs, while transfection with a miR-21-5p inhibitor antagomiR-21had the opposite effect. Moreover, the ratio of Treg/Th1 cells differentiated from peripheral blood mononuclear cells (PBMCs) decreased after being transfected with mimics, and increased with the inhibitor. AntagomiR-21 significantly relieved the lesions in colons of mice with TNBS-induced colitis, accompanied by the upregulation of PTEN and downregulation of mTOR. Inhibition of miR-21 also effectively suppressed the process of epithelial-mesenchymal transition (EMT) in vivo. In conclusion, the level of miR-21 decreased in CD, resulting in an upregulated PI3K-Akt-mTOR signaling pathway, compromised immune tolerance, and elevated inflammation.