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 journalArticle

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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
Externally publishedYes

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Intestinal Mucosa
Phosphotransferases
Epithelial Cells
Radiation Protection
Apoptosis
Radiotherapy
Radiation-Protective Agents
Radiation
Intestines
Lipopolysaccharides
Neoplasms
Transcription Factors
Wounds and Injuries
Proteins

ASJC Scopus subject areas

  • General

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IκB-kinaseβ-dependent NF-κB activation provides radioprotection to the intestinal epithelium. / Egan, Laurence J.; Eckmann, Lars; Greten, Florian R.; Chae, Sungwon; Li, Zhi Wei; Myhre, Gennett M.; Robine, Sylvie; Karin, Michael; Kagnoff, Martin F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 8, 22.02.2004, p. 2452-2457.

Research output: Contribution to journalArticle

Egan, Laurence J. ; Eckmann, Lars ; Greten, Florian R. ; Chae, Sungwon ; Li, Zhi Wei ; Myhre, Gennett M. ; Robine, Sylvie ; Karin, Michael ; Kagnoff, Martin F. / IκB-kinaseβ-dependent NF-κB activation provides radioprotection to the intestinal epithelium. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 8. pp. 2452-2457.
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