结肠炎
促炎细胞因子
细胞凋亡
癌症研究
趋化因子
肿瘤坏死因子α
下调和上调
细胞生物学
炎症
激酶
免疫学
医学
化学
生物
生物化学
基因
作者
Wenlong Lin,Chunmei Ma,Fasheng Su,Yu Jiang,Rongrong Lai,Ting Zhang,Kai Sun,Liping Fan,Zijian Cai,Zhongqi Li,He Huang,Jun Li,Xiaojian Wang
出处
期刊:Gut
[BMJ]
日期:2016-01-22
卷期号:66 (4): 597-610
被引量:52
标识
DOI:10.1136/gutjnl-2015-310096
摘要
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.
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