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-kappaB in protection against radiation-induced apoptosis in the intestinal epithelium in vivo. We use mice in which NF-kappaB signaling through IkappaB-kinase (IKK)-beta is selectively ablated in intestinal epithelial cells to show that failure to activate epithelial cell NF-kappaB 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 IKKbeta-deficient intestinal epithelial cells. Increased apoptosis in IKKbeta-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-kappaB system in protection against radiation-induced death in the intestinal epithelium in vivo and identify IKKbeta as a key molecular target for radioprotection in the intestine. Selective preactivation of NF-kappaB through IKKbeta in intestinal epithelial cells could provide a therapeutic modality that allows higher doses of radiation to be tolerated during cancer radiotherapy.
journal_name
Proc Natl Acad Sci U S Aauthors
Egan LJ,Eckmann L,Greten FR,Chae S,Li ZW,Myhre GM,Robine S,Karin M,Kagnoff MFdoi
10.1073/pnas.0306734101keywords:
subject
Has Abstractpub_date
2004-02-24 00:00:00pages
2452-7issue
8eissn
0027-8424issn
1091-6490pii
101/8/2452journal_volume
101pub_type
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