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Am J Physiol Gastrointest Liver Physiol 277: G702-G708, 1999;
0193-1857/99 $5.00
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Vol. 277, Issue 3, G702-G708, September 1999

Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice

Alix de la Coste1, Monique Fabre, Nathalie McDonell1, Arlette Porteu1, Helène Gilgenkrantz1, Christine Perret1, Axel Kahn1, and Alexandre Mignon1

1 Institut National de la Sante et de la Recherche Medicale, U-129 Institut Cochin de Genetique Moleculaire, Université Paris V René Descartes, 75014 Paris; and Hôpital du Kremlin Bicêtre, 94275 Le Kremlin-Bicêtre, France

Fas ligand (CD95L) and tumor necrosis factor-alpha (TNF-alpha ) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various 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-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing BCL-XL in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous Bcl-xL or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-alpha caused massive apoptosis and death only when transcription was inhibited. Under these conditions, PK-BCL-XL mice were partially protected from liver injury 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 activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-alpha receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.

Fas/CD95; tumor necrosis factor-alpha ; apoptosis


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