Gastrointestinal cells of IL-7 receptor null mice exhibit increased sensitivity to irradiation.
IL-7 is a critical cytokine in the development of T and B cells but little is known about its activity on nonhematopoietic cells. An unexpected finding was noted in allogeneic bone marrow transplant studies using IL-7 receptor null (IL-7R alpha(-/-)) mice as recipients. These mice exhibited a significantly greater weight loss after total body irradiation compared with wild type, IL-7R alpha(+/+), mice. Pathological assessment indicated greater intestinal crypt damage in IL-7R alpha(-/-) recipients, suggesting these mice may be predisposed to gut destruction. Therefore, we determined the effect of the conditioning itself on the intestinal tract of these mice. IL-7R alpha(-/-) mice and IL-7R alpha(+/+) mice were irradiated and examined for lesions and apoptosis within the small intestine. In moribund animals, IL-7R alpha(-/-) mice had extensive damage in the small intestine, including marked ablation of the crypts and extreme shortening of villi following 1500 cGy total body irradiation. In contrast, by 8 days after irradiation, the small intestines of IL-7R alpha(+/+) mice had regenerated as distinguished by normal villus length and hyperplastic crypts. Following 750 cGy irradiation, IL-7R alpha(-/-) mice had a higher proportion of apoptotic cells in the crypts and an accompanying increase in the pro-apoptotic protein Bak was expressed in intestinal epithelial cells. These results demonstrate the increased radiosensitivity of intestinal stem cells within the crypts in IL-7R alpha(-/-) mice and a role for IL-7 in the protection of radiation-induced apoptosis in these same cells. This study describes a novel role of IL-7 in nonhematopoietic tissues.
Welniak
L A
LA
Laboratory of Leukocyte Biology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
Khaled
A R
AR
Anver
M R
MR
Komschlies
K L
KL
Wiltrout
R H
RH
Durum
S
S
Ruscetti
F R
FR
Blazar
B R
BR
Murphy
W J
WJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D007421:Intestine, Small / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000528:radiation effects*; D014184:Transplantation, Homologous; D015431:Weight Loss / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D014916:Whole-Body Irradiation; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein