de la Coste A, Fabre M, McDonell N, Porteu A, Gilgenkrantz H, Perret C, Kahn A, Mignon A
Institut National de la Sante et de la Recherche Medicale, U-129 Institut Cochin de Genetique Moleculaire, Université Paris V René Descartes, 75014 Paris, France.
Am J Physiol. 1999 Sep;277(3):G702-8. doi: 10.1152/ajpgi.1999.277.3.G702.
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配体（CD95L）和肿瘤坏死因子-α（TNF-α）是肝细胞凋亡的关键诱导因子。这两个系统的失控激活与多种形式的肝损伤有关。尽管Bcl-2和Bcl-xL在各种凋亡途径中的广泛抗凋亡作用已得到明确证实，但其抑制Fas/CD95和TNF-α介导的凋亡信号的能力仍存在争议。我们已经证明，肝细胞中BCL-2的表达可保护转基因小鼠免受Fas诱导的暴发性肝炎。本研究表明，肝细胞中过表达BCL-XL的转基因小鼠也能以剂量依赖的方式免受Fas诱导的凋亡。Bcl-xL和Bcl-2具有保护作用，而内源性Bcl-xL或Bax水平无任何变化，并抑制肝caspase-3样活性。仅当转录受到抑制时，体内注射TNF-α才会导致大量凋亡和死亡。在这些条件下，PK-BCL-XL小鼠受到部分保护，免受肝损伤和死亡，但PK-BCL-2小鼠则不然。当Fas/CD95被激活且转录受阻时，观察到Bcl-xL和Bcl-2转基因具有类似的差异保护作用。这些结果表明，Fas/CD95和TNF-α受体激活引发的凋亡在一定程度上被转录依赖性保护作用所抵消，这对于Bcl-2而非Bcl-xL的抗凋亡活性至关重要。因此，Bcl-xL和Bcl-2在肝脏中似乎具有不同的抗凋亡作用，对其特性的表征可能有助于它们用于预防肝细胞的失控凋亡。
