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

Exposure of mice to total body irradiation induces nuclear factor B (NF B) activation in a tissue-specific manner. In addition to the spleen, lymph nodes, and bone marrow, the tissues that exhibit NF B activation now include the newly identified site of the intestinal epithelial cells. NF B activated by total body irradiation mainly consists of NF B p50/RelA heterodimers, and genetically targeted disruption of the NF B p50 gene in mice significantly decreased the activation. By comparing tissue damage and lethality in wild-type and NF B p50 knockout (p50 / ) mice after they were exposed to increasing doses of total body irradiation, we additionally examined the role of NF B activation in total body irradiationinduced 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 LD50/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 irradiationinduced 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 NF B selectively protects the small intestine against ionizing radiationinduced damage.