Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade
Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade
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DOI：
10.1053/j.gastro.2008.03.009
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发表时间：
2008-06-01
期刊：
影响因子：
29.4
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Shah, Yatrik M.;Ito, Shinji;Gonzalez, Frank J.
背景与目的：结肠上皮。细胞对于屏障功能是至关重要的，并且包含高度发达的免疫应答。以前的研究表明，缺氧诱导因子（HIF）作为一个关键的调节屏障保护在结肠上皮损伤。然而，HIF信号在结肠粘膜免疫中的作用尚不清楚。研究方法：通过使用cre/loxP技术，产生了von Hippel-Lindau肿瘤抑制蛋白（Vhl）、缺氧诱导因子（Hif）-1 α和芳烃核转运蛋白（Arnt）的细胞特异性破坏。使用葡聚糖硫酸钠（DSS）诱导的结肠炎模型诱导结肠炎症，并通过组织学分析、蛋白质印迹分析和定量聚合酶链反应分析小鼠。结果如下：在小鼠中，Vhl的结肠上皮破坏导致HIF的组成型表达，其引发结肠中炎性浸润和水肿的增加。通过破坏Vh 1和Arnt/Hif 1 β（使HIF失活），这些作用在小鼠中得到改善。在DSS诱导的结肠炎模型中，HIF表达增加与更严重的临床症状和组织学损伤增加相关，而结肠上皮中Vhl和Arnt的破坏抑制了这些作用。此外，具有HIF组成性激活的结肠显示促炎介质的表达增加，所述促炎介质在DSS给药后协同增强，并且通过抑制促炎和直接HIF靶基因巨噬细胞迁移抑制因子而减少。结论：目前的研究表明，结肠上皮细胞中HIF信号的慢性增加引发了炎症反应，这可能对开发炎症性肠病的治疗策略具有重要意义。
Backgground & Aims: Colon epithelial. cells are critical for barrier function and contain a highly developed immune response. A previous study has shown hypoxia-inducible factor (HIF) as a critical regulator of barrier protection during colon epithelial injury. However, the role of HIF signaling in colon mucosal immunity is not known. Methods: With the use of cre/loxP technology, intestinal-specific disruption of von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (Hif)-1 alpha, and aryl hydrocarbon nuclear translocator (Arnt) was generated. Colon inflammation was induced using a dextran sulfate sodium (DSS)-induced colitis model, and the mice were analyzed by histologic analysis, Western blot analysis, and quantitative polymerase chain reaction. Results: In mice, colonic epithelium disruption of Vhl resulted in constitutive expression of HIF, which initiated an increase in inflammatory infiltrates and edema in the colon. These effects were ameliorated in mice by disruption of both Vh1 and Arnt/Hif1 beta (which inactivates HIF). In a DSS-induced colitis model, increased HIF expression correlated with more severe clinical symptoms and an increase in histologic damage, while disruption of both Vhl and Arnt in the colon epithelium inhibited these effects. Furthermore, colons with constitutive activation of HIF displayed increased expression of proinflammatory mediators that were synergistically potentiated following DSS administration and reduced by inhibition of the proinflammatory and direct HIF target gene macrophage migration inhibitory factor. Conclusions: The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.