Tumor suppressor FOXO3 participates in the regulation of intestinal inflammation.
Tumor suppressor FOXO3 participates in the regulation of intestinal inflammation.
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DOI：
10.1038/labinvest.2009.66
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发表时间：
2009-09
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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炎症性肠病(IBD)包括克罗恩病和溃疡性结肠炎，以慢性黏膜损伤和炎性细胞浸润为特征。肿瘤抑制因子FOXO_3调节基因的表达，其移位到胞浆导致其转录功能的丧失。我们之前已经证明，细菌感染调节肠道上皮细胞中的FOXO_3，并增加细胞因子水平。由于肿瘤坏死因子α是肠道炎症的主要贡献者，本研究旨在评价其对FOXO_3及FOXO_3在体内外对肠道炎症的贡献的影响。肿瘤坏死因子α诱导核FOXO_3移位到胞浆中，在那里它在人肠道HT-29细胞中经历蛋白酶体的降解。在近端，PI3K和IKK通路介导了肿瘤坏死因子α诱导的FOXO_3磷酸化。在FOXO_3沉默的HT-29细胞中，肿瘤坏死因子α诱导的IL-8表达增加83%∼。在体内，Foxo3存在于结肠隐窝上皮细胞的胞核和胞浆中。在DSS诱导的结肠炎模型中，FOXO_3‘S的核定位缺失，仅见于胞浆中。与Foxo3在结肠炎中的作用一致，接受DSS治疗的Foxo3缺陷小鼠比野生型小鼠出现更严重的结肠炎，上皮内淋巴细胞和中性粒细胞渗入的数量增加。综上所述，肿瘤坏死因子α通过PI3K和IKK途径灭活肠上皮细胞中的FOXO_3，FOXO_3在体外失活导致IL-8上调；在体内，FOXO_3存在于炎症的结肠上皮细胞胞浆中，FOXO_3缺乏会导致严重的肠道炎症。
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic mucosal injury and the infiltration of inflammatory cells. Tumor suppressor FOXO3 regulates gene expression and its translocation to the cytosol leads to the abrogation of its transcriptional function. We have previously shown that bacterial infection regulates FOXO3 in intestinal epithelial cells and increases cytokine levels. As TNFα is a major contributor in intestinal inflammation, the aim of this study was to assess its effect on FOXO3 and FOXO3's contribution to intestinal inflammation in vitro and in vivo. TNFα induces the translocation of nuclear FOXO3 into the cytosol where it undergoes proteasomal degradation in human intestinal HT-29 cells. Proximally, the PI3K and IKK pathways mediate TNFα-induced FOXO3 phosphorylation. In FOXO3-silenced HT-29 cells, TNFα-induced IL-8 expression is increased ∼83%. In vivo, Foxo3 is present in the nuclei and cytosol of colonic crypt epithelia. In DSS-induced colonic inflammation, Foxo3's nuclear localization is lost and it is only found in the cytosol. Consistent with a role for Foxo3 in colitis, Foxo3-deficient mice treated with DSS developed more severe colonic inflammation with an increased number of intraepithelial lymphocytes and PMNs infiltrated in the epithelia, than wild-type mice. In summary, TNFα inactivates FOXO3 in intestinal epithelia through the PI3K and IKK pathways and FOXO3 inactivation leads to the upregulation of IL-8 in vitro; in vivo Foxo3 is in the cytosol of inflamed colonic epithelia and Foxo3 deficiency leads to severe intestinal inflammation.
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影响因子：
82.9
作者：
Jonsson, H;Allen, P;Peng, SL
通讯作者：
Peng, SL
DOI：
10.1073/pnas.0405454101
发表时间：
2004-09-14
影响因子：
11.1
作者：
Aoki, M;Hao, J;Vogt, PK
通讯作者：
Vogt, PK
影响因子：
64.8
作者：
Medema, RH;Kops, GJPL;Burgering, BMT
通讯作者：
Burgering, BMT
影响因子：
29.4
作者：
BREESE, EJ;MICHIE, CA;MACDONALD, TT
通讯作者：
MACDONALD, TT
影响因子：
32.4
作者：
Lin, L;Hron, JD;Peng, SL
通讯作者：
Peng, SL