Abstract
Fas is an apoptosis–signaling cell surface antigen that has been shown to trigger cell death upon specific ligand or antibody binding. Treatment of mice with an anti–Fas antibody causes fulminant hepatic failure due to massive apoptosis. To test a putative protective effect of the anti–apoptotic Bcl–2 protein, transgenic mice were generated to express the human bcl–2 gene product in hepatocytes. Early onset of massive hepatic apoptosis leading to death was observed in all nontransgenic mice treated with an anti–Fas antibody. By contrast, hepatic apoptosis was delayed and dramatically reduced in transgenic animals, yielding a 93% survival rate. These results demonstrate that Bcl–2 is able to protect from in vivoFas–mediated cytotoxicity, and could be of significance for preventing fulminant hepatic failure due to viral hepatitis in humans.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Thompson, C.B. Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462 (1995).
Nagata, S. & Golstein, P., Fas death factor. Science 267, 1449–1456 (1995).
Suda, T. & Nagata, S. Purification and characterization of the Fas-ligand that induces apoptosis. J. Exp. Med. 179, 873–879 (1994).
Itoh, N. et al. The polypeptide encoded by the cDNA for the human cell surface antigen Fas can mediate apoptosis. Cell 66, 233–243 (1991).
Trauth, B.C. et al. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245, 301–304 (1989).
Rouvier, E., Luciani, M.F. & Golstein, P. Fas involvement in Ca2+-independent T cell-mediated cytotoxicity. J. Exp. Med. 177, 195–200 (1993).
Kagi, D. et al. Fas and perform pathways as major mechanisms of T cell-mediated cytotoxiclty. Science 265, 528–530 (1994).
Watanabe-Fukunaga, R., Brannan, C.I., Copeland, N.G., Jenkins, N.A. & Nagata, S. Lymphoproliferative disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356, 314–317 (1992).
Takahashi, T. et al. Generalized lymphoproliferative disease in mice caused by a point mutation in the Fas ligand. Cell 76, 969–976 (1994).
Rieux-Laucat, F. et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268, 1347–1349 (1995).
Fisher, G.H. et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81, 935–946 (1995).
Zornig, M., Grzeschiczek, A., Kowalski, M.B., Hartmann, K.U. & Moroy, T. Loss of Fas/APO-1 receptor accelerates lymphomagenesis in Em L-Myc transgenic mice but not in animals infected with MoMuLV. Oncogene 10, 2397–2401 (1995).
Weller, M., Malipiero, U., Aguzzi, A., Reed, J.C. & Fontana, A., Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drags and therapeutic irradiation. J. Clin. Invest. 95, 2633–2643 (1995).
Watanabe, D., Suda, T., Hashimoto, H. & Nagata, S. Constitutive activation of the Fas ligand gene in mouse lymphoproliferative disorders. EMBO J. 14, 12–18 (1995).
Hiramatsu, N. et al. Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology 19, 1354–1359 (1994).
Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).
Cleveland, J.L. & Ihle, J.N. Contenders in FasL/TNF death signalling. Cell 81, 479–482 (1995).
Enari, M., Hug, H. & Nagata, S. Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature 375, 78–81 (1995).
Los, M. et al. Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis. Nature 375, 81–83 (1995).
Korsmeyer, S.J. Regulators of cell death. Trends Genet. 11, 101–104 (1995).
Itoh, N., Tsujimoto, Y. & Nagata, S. Effect of Bcl-2 on Fas antigen-mediated cell death. J. Immunol. 151, 621–627 (1993).
Chiu, V.K., Walsh, C.M., Liu, C.C., Reed, J.C. & Clark, W.R. Bcl-2 blocks degranulation but not Fas-based cell-mediated cytotoxicity. J. Immunol. 154, 2023–2032 (1995).
Vaux, D.L., Aguila, H.L. & Weissman, I.L. Bcl-2 prevents death of factor deprived cells but fails to prevent apoptosis in targets of cell-mediated killing. Int. Immunol. 4, 821–826 (1992).
Tsujimoto, Y. & Croce, C.M. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl. Acad. Sci. USA 83, 5214–5218 (1986).
Miquerol, L. et al. Expression of the L-type pyruvate kinase gene and the hepatocyte nuclear factor 4 transcription factor in exocrine and endocrine pancreas. J. Biol. Chem. 269, 8944–8951 (1994).
Watanabe-Fukunaga, R. et al. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J. Immunol. 148, 1274–1279 (1992).
Tsujimoto, Y., Cossman, J., Jaffe, E. & Croce, C.M. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228, 1440–1443 (1985).
Reed, J.C. Bcl-2 and the regulation of programmed cell death. J. Cell. Biol. 124, 1–6 (1994).
Zhao, M., Zhang, N.X., Economou, M., Laissue, J.A. & Zimmerman, A. Immunohistochemical detection of Bcl-2 protein in liver lesions: Bcl-2 protein is expressed in hepatocellular carcinomas but not in liver cell dysplasia. Histopathology 25, 237–245 (1994).
Krajewski, S. et al. Immunohistochemical determination of in vivodistribution of Bax, a dominant inhibitor of Bcl-2. Am. J. Pathol. 145, 1323–1336 (1994).
Kiefer, M.C. et al. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature 374, 736–739 (1995).
Oltvai, Z.N. & Korsmeyer, S.J. Checkpoints of dueling dimers foil death wishes. Cell 79, 189–192 (1994).
Oltvai, Z.N., Milliman, C.L. & Korsmeyer, S.J. Bcl-2 heterodimerizes in vivowith a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609–619 (1993).
Yang, E. et al. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285–291 (1995).
Boise, L.H. et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608 (1993).
Mita, E. et al. Role of Fas ligand in apoptosis induced by hepatitis C virus infection. Biochem. Biophys. Res. Commun. 204, 468–474 (1994).
Rehermann, B. et al. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J. Exp. Med. 181, 1047–1058 (1995).
Ando, K. et al. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J. Exp. Med. 178, 1541–1554 (1993).
Takahashi, H., Fujimoto, J., Hanada, S. & K J.Acute hepatitis in rats expressing human hepatitis B virus transgenes. Proc. Natl. Acad. Sci. USA 92, 1470–1474 (1995).
Lacronique, V. et al. Identification and functional characterization of an erythroid-specific enhancer in the L-type pyruvate kinase gene. J. Biol. Chem. 270, 14989–14997 (1995).
Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J. & WJ.Isolation of biologically active ribonucleic acid from sources enriched in ribonucleases. Biochemistry 18, 5294–5299 (1979).
Giannini, G. et al. The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J. Cell Biol. 128, 893–904 (1995).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lacronique, V., Mignon, A., Fabre, M. et al. Bcl–2 protects from lethal hepatic apoptosis induced by an ant–Fas antibody in mice. Nat Med 2, 80–86 (1996). https://doi.org/10.1038/nm0196-80
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0196-80
This article is cited by
-
Moderate chronic ethanol consumption exerts beneficial effects on nonalcoholic fatty liver in mice fed a high-fat diet: possible role of higher formation of triglycerides enriched in monounsaturated fatty acids
European Journal of Nutrition (2020)
-
Interferon-α-inducible Dendritic Cells Matured with OK-432 Exhibit TRAIL and Fas Ligand Pathway-mediated Killer Activity
Scientific Reports (2017)
-
Antitherapeutic antibody-mediated hepatotoxicity of recombinant human Apo2L/TRAIL in the cynomolgus monkey
Cell Death & Disease (2016)
-
Osteopontin deficiency aggravates hepatic injury induced by ischemia–reperfusion in mice
Cell Death & Disease (2014)
-
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
Archives of Toxicology (2013)