The Function Of Raf Kinase Inhibitor Protein RKIP In Human And Mice Colitis

Objective Raf kinase inhibitor protein (RKIP) appears to control cancer cell metastasis and its expression in colonic tissue is related to colonic cancer development. We sought to identify the roles of RKIP in maintaining homeostasis of gastrointestinal tract.Design The expression of RKIP was determined by immunohistochemistry and western-blot analysis. RKIP knock-out (KO) and wild-type (WT) mice were administered dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis, and the mice were assessed based on colitis symptoms and biochemical approaches. The mechanism was analyzed using immunoprecipitation and pull-down experiments.Results The RKIP expression is positively correlated with the severity of inflammatory bowel disease (IBD). RKIP deficiency protects mice from dextran sulfate sodium (DSS)-or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis and accelerated recovery from colitis. RKIP deficiency inhibits DSS-induced infiltration of acute-phase immune cells and reduces production of proinflammatory cytokines and chemokines in colon. RKIP deficiency inhibits DSS-or TNBS-induced colonic epithelial barrier damage and intestinal epithelial cell (IEC) apoptosis. RKIP deficiency also inhibits TNF-a induced IEC apoptosis and colitis. Mechanistically, RKIP enhances the induction of P53-upregulated modulator of apoptosis (PUMA) by interacting with TGF-β-activated kinase 1(TAK1) and promoting TAK1-mediated NF-κB activation. This is supported by the observation that TAK1 activation is positively correlated with the expression of RKIP in human clinical samples and the development of IBD.Conclusions RKIP contributes to colitis development by promoting inflammation and mediating IEC apoptosis and might represent a therapeutic target of IBD.