IκB-kinaseβ-dependent NF-κB activation provides radioprotection to the intestinal epithelium

Laurence J. Egan, Lars Eckmann, Florian R. Greten, Sungwon Chae, Zhi Wei Li, Gennett M. Myhre, Sylvie Robine, Michael Karin, Martin F. Kagnoff

    Research output: Contribution to journalArticlepeer-review

    166 Citations (Scopus)

    Abstract

    Acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiation therapy. We studied the role of the transcription factor NF-κB in protection against radiation-induced apoptosis in the intestinal epithelium in vivo. We use mice in which NF-κB signaling through IκB-kinase (IKK)-β is selectively ablated in intestinal epithelial cells to show that failure to activate epithelial cell NF-κB in vivo results in a significant increase in radiation-induced epithelial cell apoptosis. Furthermore, bacterial lipopolysaccharide, which is normally a radioprotective agent, is radiosensitizing in IKKβ-deficient intestinal epithelial cells. Increased apoptosis in IKKβ-deficient intestinal epithelial cells was accompanied by increased expression and activation of the tumor suppressor p53 and decreased expression of antiapoptotic Bcl-2 family proteins. These results demonstrate the physiological importance of the NF-κB system in protection against radiation-induced death in the intestinal epithelium in vivo and identify IKKβ as a key molecular target for radioprotection in the intestine. Selective preactivation of NF-κB through IKKβ in intestinal epithelial cells could provide a therapeutic modality that allows higher doses of radiation to be tolerated during cancer radiotherapy.

    Original languageEnglish
    Pages (from-to)2452-2457
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume101
    Issue number8
    DOIs
    Publication statusPublished - 2004 Feb 22

    ASJC Scopus subject areas

    • General

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