Inhibition of Pim-1 Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

Abstract

Pim-1 kinase is involved in the control of cell growth, differentiation and apoptosis. Recent evidence suggests that Pim kinases play a role in immune regulation and inflammation. However, the role of Pim-1 kinase in inflammatory bowel diseases (IBD) remains unclear. The aims of this study were to explore the role of Pim-1 kinase in the pathology of IBD and to assess whether inhibiting Pim-1 kinase may be of therapeutic benefit as a treatment regimen for IBD. Colitic mouse model was established by the induction of dextran sodium sulfate. The expression of Pim-1 in the colonic samples of control and colitic mice was examined. Furthermore, the mice were treated with Pim-1inhibitor (PIM-Inh), then the body weight and colon inflammation were evaluated, and the production of cytokines including IFN-γ, IL-4, TGF-β and IL-17 in colon tissues was determined by ELISA. The expression of T cell master transcription factors T-bet, ROR-γt, GATA-3 and Foxp3 and Nuclear factor κB (NF-κB) and inducible nitric oxide synthase in colon tissues was detected by real-time PCR and western blot. Finally, the effect of LPS on Pim-1 expression and the effects of PIM-Inh on LPS-induced upregualtion of p65 and TNF-α in RAW264.7 cells were examined by real-time PCR and western blot. Pim-1 expression was correlated with the degree of mucosal inflammation in vivo, and it was significantly induced by LPS in vitro. PIM-Inh had protective effects on acute colitis in vivo. Mechanistically, PIM-Inh reduced the proinflammatory immune response through the inhibition of the overactivation of macrophages and the down-regulation of excessive Th1- and Th17-type immune responses. Furthermore, PIM-Inh could skew T cell differentiation towards a Treg phenotype. Pim-1 kinase is involved in mucosal injury/inflammation and Pim-1 kinase inhibitor may provide a novel therapeutic approach for IBD.