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.
Egan
Laurence J
LJ
Laboratory of Mucosal Immunology, University of California at San Diego, La Jolla, CA 92093, USA.
Eckmann
Lars
L
Greten
Florian R
FR
Chae
Sungwon
S
Li
Zhi-Wei
ZW
Myhre
Gennett M
GM
Robine
Sylvie
S
Karin
Michael
M
Kagnoff
Martin F
MF
D000818:Animals; D051550:I-kappa B Kinase; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000528:radiation effects*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000528:radiation effects*; D011835:Radiation Protection; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008070:Lipopolysaccharides; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse