Host: The Japan Radiation Research Society
Although high-dose radiation exposed to whole body results in gastrointestinal injury and finally leads to death, a real effective radioprotector has not yet been established. Ursodeoxycholic acid (UDCA), a major component of bear bile, has been widely used to treat pain, inflammation, and hepatobiliary diseases. Recently, several potential mechanisms of the anti-apoptotic action of UDCA have been proposed, including inhibition of mitochondrial membrane depolarization and enhancement of methionine adenosyltransferase activity. In the present study, we investigated whether UDCA can protect rat intestinal epithelial IEC-6 cells from high-dose irradiation. IEC-6 cells were cultured in DMEM with 5% FCS and were treated with 50, 100, and 200 microM UDCA alone or in combination with inhibitors of MEK and p38 MAPK or PI3K, and irradiated with gamma rays at a dose of 20 Gy. Analyses using Hoechst staining showed that UDCA suppressed radiation-induced apoptosis of the cells in a dose-dependent manner. UDCA in the presence of an inhibitor of MEK further decreased the number of apoptotic cells, whereas PI3K inhibitor attenuated the anti-apoptotic effects of UDCA. Western blot analyses showed that treatment with UDCA inhibited phosphorylation of ERK, enhanced phosphorylation of Akt, but did not affect p38 MAPK phosphorylation in irradiated IEC-6 cells. UDCA also increased expression of Bcl-2 and Bcl-xL and suppressed caspase 9 activation, but did not change expression of Bax and cytochrome c. In conclusion, UDCA protects intestinal cells from irradiation-induced apoptosis in vitro through inhibition of the MEK/ERK pathway, activation of the PI3K/Akt pathway, and via inhibition of caspase/mitochondria pathways.
