FoxO4 inhibits NF-kappaB and protects mice against colonic injury and inflammation.
FoxO4 inhibits NF-kappaB and protects mice against colonic injury and inflammation.
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DOI：
10.1053/j.gastro.2009.06.049
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发表时间：
2009-10
期刊：
影响因子：
29.4
通讯作者：
Liu ZP
中科院分区：
文献类型：
--
作者：
Zhou W;Cao Q;Peng Y;Zhang QJ;Castrillon DH;DePinho RA;Liu ZP
FoxO 4是叉头盒转录因子O（FoxO）亚家族的成员。FoxO蛋白参与多种生物过程。在这项研究中，我们研究了FoxO 4在肠粘膜免疫和炎症性肠病（IBD）中的作用。对Foxo 4缺失小鼠进行三硝基苯磺酸（TNBS）处理。微阵列分析和定量RT-PCR用于鉴定Foxo 4缺失改变的细胞因子转录本。采用荧光染料渗透法和免疫印迹法检测Foxo 4缺陷对肠上皮细胞通透性和紧密连接蛋白水平的影响。通过免疫学和生物化学分析，探讨了FoxO 4调节粘膜免疫的分子和细胞机制。采用免疫组织化学方法检测IBD患者肠上皮细胞FoxO 4的表达水平。Foxo 4缺失小鼠对TNBS损伤诱导的结肠炎更敏感。趋化因子CCL 5在Foxo 4基因敲除小鼠的结肠上皮细胞中显著上调，结肠中CD 4+上皮内T细胞的募集增加，细胞因子INFγ和TNFα上调。Foxo 4缺乏还导致肠上皮通透性增加和紧密连接蛋白ZO-1和claudin-1下调。在机制上，FoxO 4抑制NF-κB的转录活性，并且FoxO 4缺陷与体内NF-κB活性增加相关。FoxO 4转录在TNBS治疗和IBD患者中被短暂抑制。这些结果表明，FoxO 4是NF-κB的内源性抑制剂，并确定了FoxO 4在调节NF-κB介导的粘膜免疫中的新功能。
FoxO4 is a member of the forkhead box transcription factor O (FoxO) subfamily. FoxO proteins are involved in diverse biological processes. In this study, we examine the role of FoxO4 in intestinal mucosal immunity and inflammatory bowel disease (IBD). Foxo4-null mice were subjected to trinitrobenzene sulfonic acid (TNBS)-treatment. Microarray analysis and quantitative RT-PCR were used to identify the cytokine transcripts that were altered by Foxo4-deletion. The effects of Foxo4-deficiency on the intestinal epithelial permeability and levels of tight junction proteins were examined by permeable fluorescent dye and western blot. The molecular and cellular mechanism(s) by which FoxO4 regulates the mucosal immunity were explored through immunological and biochemical analyses. The expression level of FoxO4 in intestinal epithelial cells of patients with IBD was examined using immunohistochemistry. Foxo4-null mice were more susceptible to TNBS injury induced colitis. The chemokine CCL5 is significantly up-regulated in the colonic epithelial cells of Foxo4-null mice, with increased recruitment of CD4+ intraepithelial T cells and up-regulation of cytokines INFγ and TNFα in the colon. Foxo4-deficiency also resulted in an increase in intestinal epithelial permeability and downregulation of the tight junction proteins ZO-1 and claudin-1. Mechanistically, FoxO4 inhibited the transcriptional activity of NF-κB and Foxo4-deficiency is associated with increased NF-κB activity in vivo. FoxO4 transcription is transiently repressed in response to TNBS treatment and in patients with IBD. These results indicate that FoxO4 is an endogenous inhibitor of NF-κB and identify a novel function of FoxO4 in the regulation of NF-κB mediated mucosal immunity.
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