論文

査読有り
2008年6月

Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade

GASTROENTEROLOGY
  • Yatrik M. Shah
  • ,
  • Shinji Ito
  • ,
  • Keiichirou Morimura
  • ,
  • Chi Chen
  • ,
  • Sun-Hee Yim
  • ,
  • Volker H. Haase
  • ,
  • Frank J. Gonzalez

134
7
開始ページ
2036
終了ページ
2048
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1053/j.gastro.2008.03.009
出版者・発行元
W B SAUNDERS CO-ELSEVIER INC

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.

Web of Science ® 被引用回数 : 123

リンク情報
DOI
https://doi.org/10.1053/j.gastro.2008.03.009
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000256686400028&DestApp=WOS_CPL
ID情報
  • DOI : 10.1053/j.gastro.2008.03.009
  • ISSN : 0016-5085
  • Web of Science ID : WOS:000256686400028

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