NFκB-mediated upregulation of bcl-xl restrains TRAIL-mediated apoptosis in murine viral hepatitis†

Inhibition of NFκB enhances the susceptibility of cancer to TRAIL-mediated apoptosis and is suggested as a strategy for cancer therapy. Because the role of NFκB in TRAIL-mediated apoptosis of hepatocytes is unknown, we investigated the influence of NFκB-inhibition in death ligand-mediated apoptosis in hepatitis. Adenoviral hepatitis resulted in upregulation of NFκB-activity, which could be inhibited by expression of IκBα-superrepressor. We treated mice after the onset of adenoviral hepatitis with adenoviruses expressing FasL (AdFasL), TRAIL (AdTRAIL), or GFP (AdGFP). In contrast to apoptosis induced by AdFasL, NFκB inhibition strongly enhanced AdTRAIL-mediated apoptosis of hepatocytes. Expression of IκBα inhibits adenoviral infection-mediated overexpression of bcl-xl, providing a molecular mechanism for TRAIL sensitization. In agreement with this hypothesis, downregulation of bcl-xl by siRNA enhanced susceptibility of hepatocytes to TRAIL, but not to FasL-mediated apoptosis, resulting in TRAIL-mediated severe liver damage after AdTRAIL application. Our data demonstrate that inhibition of NFκB in adenoviral hepatitis strongly sensitizes hepatocytes to TRAIL-mediated apoptosis. Bcl-xl, in contrast to bcl-2 and c-FLIP, is strongly upregulated after viral infection and represents an essential NFκB-dependent survival factor against TRAIL-mediated apoptosis. In conclusion, inhibition of NFκB or bcl-xl during TRAIL therapy may harbor a risk of liver damage in patients with viral hepatitis. (HEPATOLOGY 2005;41:280–288.)