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Gastrointestinal Cells of IL-7 Receptor Null Mice Exhibit Increased Sensitivity to Irradiation¹

Lisbeth A. Welniak^*, Annette R. Khaled, Miriam R. Anver, Kristin L. Komschlies, Robert H. Wiltrout, Scott Durum, Francis R. Ruscetti^*, Bruce R. Blazar^¶ and William J. Murphy^2,

^* Laboratories of Leukocyte Biology, Molecular Immunoregulation, and Experimental Immunology, Division of Basic Sciences, and Intramural Research Support Program, Science Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702; and ^¶ Department of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN 55455

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^-/-) mice as recipients. These mice exhibited a significantly greater weight loss after total body irradiation compared with wild type, IL-7R^+/+, mice. Pathological assessment indicated greater intestinal crypt damage in IL-7R^-/- 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^-/- mice and IL-7R^+/+ mice were irradiated and examined for lesions and apoptosis within the small intestine. In moribund animals, IL-7R^-/- 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^+/+ mice had regenerated as distinguished by normal villus length and hyperplastic crypts. Following 750 cGy irradiation, IL-7R^-/- 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^-/- 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.