Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

Gut radiation-induced injury is a concern during treatment of patients with cancer. Krüppel-like factor 4 (KLF4) is expressed in differentiated villous epithelial cells of the small intestine. We previously showed that KLF4 protects cells from apoptosis following 7-irradiation in vitro. We sought to determine whether KLF4 mediates the small intestinal response to 7-irradiation in vivo. Mice with intestinal epithelium-specific deletion of Klf4 (Klf4^AIS) and control (Klf4^{fl/ fl}) mice were irradiated with total-body 7-radiation. Following irradiation, the Klf4^AIS mice had significantly increased mortality compared with irradiated Klf4^{fl / fl} mice. Immuno-histochemistry and immunofluorescence staining were used to assess the morphological changes, levels of proliferation, and apoptosis in the intestinal epithelium. At 96 h following irradiation, there was a regenerative response manifested by an expansion of the proliferative zone in both mouse groups, with the control mice having a higher proliferative activity than the Klf4^AIS group. In addition, there was a significant increase in the number of Klf4/Ki67-copositive cells in the irradiated control mice compared with unirradiated mice. Also, the irradiated Klf4^AIS mice had a significantly higher number of crypt cells positive for apoptosis, p53, and p21 compared with irradiated Klf4^fl/fl mice. Taken together, our data suggest that Klf4 may function as a radioprotective factor against gastrointestinal syndrome in mice following 7-irradiation by inhibiting apoptosis in the acute response to irradiation and contributing to crypt regeneration.