Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice.
Am J Physiol
; 277(3): G702-8, 1999 09.
Article
em En
| MEDLINE
| ID: mdl-10484397
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-bcl-2
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Am J Physiol
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
França