Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice
Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice
复制标题
Raf 激酶抑制剂蛋白介导肠上皮细胞凋亡并促进人类和小鼠的 IBD。
DOI：
10.1136/gutjnl-2015-310096
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发表时间：
2017-04-01
期刊：
影响因子：
24.5
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
--
作者：
Lin, Wenlong;Ma, Chunmei;Wang, Xiaojian
目的Raf激酶抑制蛋白（Raf kinase inhibitor protein，RKIP）控制癌细胞的转移，其在结肠组织中的表达与结肠癌的发生发展有关。我们试图确定RKIP在维持胃肠道内稳态中的作用。设计RKIP的表达通过免疫组织化学和蛋白质印迹分析来确定。给予RKIP敲除小鼠和野生型小鼠葡聚糖硫酸钠（DSS）或2，4，6-三硝基苯磺酸（TNBS）以诱导实验性结肠炎，并基于结肠炎症状和生化方法评估小鼠。结果RKIP的表达与IBD的严重程度呈正相关。RKIP缺乏可保护小鼠免受DSS或TNBS诱导的结肠炎并加速结肠炎的恢复。RKIP缺陷抑制DSS诱导的急性期免疫细胞浸润，并减少结肠中促炎细胞因子和趋化因子的产生。RKIP缺陷抑制DSS诱导或TNBS诱导的结肠上皮屏障损伤和肠上皮细胞（IEC）凋亡。RKIP缺陷还抑制肿瘤坏死因子-α诱导的IEC凋亡和结肠炎。从机制上讲，RKIP通过与TGF-β激活的激酶1（TAK 1）相互作用并促进TAK 1介导的NF-κ B激活，增强P53上调的凋亡调节剂的诱导。TAK 1的激活与RKIP在人临床样本中的表达和IBD的发展呈正相关。结论RKIP通过促进炎症和介导IEC凋亡参与结肠炎的发展，可能是IBD的治疗靶点。
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-beta-activated kinase 1 (TAK1) and promoting TAK1-mediated NF-kappa B 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.