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Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice
  1. Wenlong Lin1,
  2. Chunmei Ma1,
  3. Fasheng Su1,
  4. Yu Jiang2,
  5. Rongrong Lai1,
  6. Ting Zhang3,
  7. Kai Sun4,
  8. Liping Fan4,
  9. Zijian Cai1,
  10. Zhongqi Li5,
  11. He Huang6,
  12. Jun Li7,
  13. Xiaojian Wang1
  1. 1Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, P.R.China
  2. 2Department of Clinical Laboratory, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China
  3. 3Department of Radiation Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China
  4. 4Department of Pathology and Clinical Laboratory, The Second Affiliated Hospital, Zhejiang Chinese Medical University. Hangzhou, P.R.China
  5. 5Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China
  6. 6Bone marrow transplantation center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China
  7. 7State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China
  1. Correspondence to Dr Xiaojian Wang, Institute of Immunology, Zhejiang University, 866 Yuhang Tang Road, Medical Research Building B819, Hangzhou, Zhejiang 310058, P. R. China; wangxiaojian{at}cad.zju.edu.cn or Jun Li, Ph.D. Professor, State Key Laboratory for Diagnosis and Treatment of Infectious Disease The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Rd, Hangzhou 31000, China; lijun2009{at}zju.edu.cn

Abstract

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 GI tract.

Design The expression of RKIP was determined by immunohistochemistry and western blot analysis. RKIP knockout and wild-type 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 analysed using immunoprecipitation and pull-down experiments.

Results The RKIP expression is positively correlated with the severity of IBD. RKIP deficiency protects mice from DSS-induced or 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-induced or TNBS-induced colonic epithelial barrier damage and intestinal epithelial cell (IEC) apoptosis. RKIP deficiency also inhibits tumour necrosis factor-alpha-induced IEC apoptosis and colitis. Mechanistically, RKIP enhances the induction of P53-upregulated modulator of apoptosis 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.

  • APOPTOSIS
  • COLONIC DISEASES
  • IBD BASIC RESEARCH

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