Differential protective effects of Bcl-x(L) and Bcl-2 on apoptotic liver injury in transgenic mice

Fas ligand (CD95L) and tumor necrosis factor-alpha (TNF-alpha) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two syst ems is involved in several forms of liver injury. Although the broad antiap optotic action of Bcl-2 and Bcl-x(L) has been clearly established in variou s apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-alpha- mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induc ed fulminant hepatitis in transgenic mice. The present study shows that tra nsgenic mice overexpressing BCL-X-L, in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were pr otective without any change in the level of endogenous Bcl-xL or Ban and in hibited hepatic caspase-3-like activity. In vivo injection of TNF-alpha cau sed massive apoptosis and death only when transcription was inhibited. Unde r these conditions, PK-BCL-X-L mice were partially protected from liver inj ury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activ ated and transcription blocked. These results suggest that apoptosis trigge red by activation of both Fas/CD95 and TNF-cl receptors is to some extent c ounteracted by the transcription-dependent protective effects, which are es sential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefor e, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the l iver whose characterization could facilitate their use to prevent the uncon trolled apoptosis of hepatocytes.