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Activation of Nuclear Factor B In vivo Selectively Protects the Murine Small Intestine against Ionizing Radiation-Induced Damage

Departments of ¹ Pathology and Laboratory Medicine, ² Otolaryngology-Head and Neck Surgery, and ³ Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina; ⁴ Department of Medicine, University of Kentucky, Lexington, Kentucky; and ⁵ Veterans Administration Medical Center, Lexington, Kentucky

Exposure of mice to total body irradiation induces nuclear factor B (NFB) activation in a tissue-specific manner. In addition to the spleen, lymph nodes, and bone marrow, the tissues that exhibit NFB activation now include the newly identified site of the intestinal epithelial cells. NFB activated by total body irradiation mainly consists of NFB p50/RelA heterodimers, and genetically targeted disruption of the NFB p50 gene in mice significantly decreased the activation. By comparing tissue damage and lethality in wild-type and NFB p50 knockout (p50^–/–) mice after they were exposed to increasing doses of total body irradiation, we additionally examined the role of NFB activation in total body irradiation-induced tissue damage. The results show that p50^–/– mice are more sensitive to total body irradiation-induced lethality than wild-type mice (LD_{50/Day 7}: wild-type = 13.12 Gy versus p50^–/– = 7.75 Gy and LD_{50/Day 30}: wild-type = 9.31 Gy versus p50^–/– = 7.81 Gy). The increased radiosensitivity of p50^–/– mice was associated with an elevated level of apoptosis in intestinal epithelial cells and decreased survival of the small intestinal crypts compared with wild-type mice (P < 0.01). In addition, RelA/TNFR1-deficient (RelA/TNFR1^–/–) mice also exhibited a significant increase in intestinal epithelial cell apoptosis after they were exposed to total body irradiation as compared with TNFR1-deficient (TNFR1^–/–) mice (P < 0.01). In contrast, no significant increase in total body irradiation-induced apoptosis or tissue injury was observed in bone marrow cells, spleen lymphocytes, and the liver, heart, lung, and kidney of p50^–/– mice in comparison with wild-type mice. These findings indicate that activation of NFB selectively protects the small intestine against ionizing radiation-induced damage.

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