IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium.
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.[1]References
- IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Egan, L.J., Eckmann, L., Greten, F.R., Chae, S., Li, Z.W., Myhre, G.M., Robine, S., Karin, M., Kagnoff, M.F. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
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