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Essential roles of the Fas ligand in the development of hepatitis

Nature Medicine volume 3, pages 409–413 (1997)Cite this article

Abstract

The Fas ligand (FasL) is expressed in activated T cells and induces apoptosis in Fas-bearing cells. A cytotoxic T lymphocyte (CTL) clone specific for hepatitis B surface antigen (HBsAg) causes an acute liver disease in HBsAg transgenic mice. Here we observed that the CTL clone killed hepatocytes expressing HBsAg in a Fas-dependent manner. Administration of the soluble form of Fas into HBsAg transgenic mice prevented the CTL-induced liver disease. In the second model, mice were primed with Propionibacterium acnes. A subsequent challenge with lipopolysaccharide (LPS) killed the mice by inducing liver injury. Neutralization of FasL rescued the mice from LPS-induced mortality, and Fas-null mice were resistant to LPS-induced mortality. These results suggest that FasL has an essential role in the development of hepatitis.

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References

  1. Nagata, S. & Golstein, P., Fas death factor. Science 267, 1449–1456 (1995).

    Article  CAS  Google Scholar 

  2. Rouvier, E., Luciani, M.-F. & Golstein, P. Fas involvement in Ca2+-independentT Cell-mediated cytotoxicity. J. Exp. Med. 177, 195–200 (1993).

    Article  CAS  Google Scholar 

  3. Hanabuchi, S. et al. Fas and its ligand in a general mechanism of T-Cell mediated cy-totoxicity. Proc. Natl. Acad. Sci. USA 91, 4930–4934 (1994).

    Article  CAS  Google Scholar 

  4. Suda, T. et al. Expression of the Fas ligand in T-Cell-lineage. J. Immunol. 154, 3806–3813 (1995).

    CAS  Google Scholar 

  5. Vignaux, F. et al. TCR/CD3 coupling to Fas-based cytotoxicity. J. Exp. Med. 181, 781–786 (1995).

    Article  CAS  Google Scholar 

  6. Kägi, D. et al. Fas and perforin pathway as major mechanisms of T Cell-mediated cy-totoxicity. Science 265, 528–530 (1994).

    Article  Google Scholar 

  7. Kojima, H. et al. Two distinct pathways of specific killing revealed by perforin mu-tant cytotoxic T lymphocytes. Immunity 1, 357–364 (1994).

    Article  CAS  Google Scholar 

  8. Lowin, B., Hahne, M., Mattmann, C. & Tschopp, J. Cytolytic T-Cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370, 650–652 (1994).

    Article  CAS  Google Scholar 

  9. Watanabe-Fukunaga, R. et al. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J. Immunol. 148, 1274–1279 (1992).

    CAS  Google Scholar 

  10. Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).

    Article  CAS  Google Scholar 

  11. Hoofnagle, J., Carithers, R., Shapiro, C. & Ascher, N. Fulminant hepatic failure: Summary of a workshop. Hepatology 21, 240–252 (1995).

    CAS  PubMed  Google Scholar 

  12. Berke, G., CTL's kiss of death. Cell 81, 9–12 (1994).

    Article  Google Scholar 

  13. Rose, N.R. & Bona, C. Defining criteria for autoimmune disease (Witebsky's postu-lates revisited). Immunol. Today 14, 426–430 (1993).

    Article  CAS  Google Scholar 

  14. Ando, K. et al. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J. Exp. Med. 178, 1541–1554 (1993).

    Article  CAS  Google Scholar 

  15. Moriyama, T. et al. Immunobiology and pathogenesis of hepatoCellular injury in hepatitis B virus transgenic mice. Science 248, 361–364 (1990).

    Article  CAS  Google Scholar 

  16. Ferluga, J. & Allison, A. Role of mononuclear infiltrating Cells in pathogenesis of hepatitis. Lancet 2, 610–611 (1978).

    Article  CAS  Google Scholar 

  17. Sato, T. et al. Inhibition of Corynebacterium porvum-primed and lipopolysaccharide-induced hepatic necrosis in rats by selective depletion of neutrophils using a mono-clonal antibody. J. Leuk. Biol. 53, 144–150 (1993).

    Article  CAS  Google Scholar 

  18. Fujioka, N. et al. Preparation of specific antibodies against murine IL-1 ra and the establishment of IL-1 ra as an endogenous regulator of bacteria-induced fulminant hepatitis in mice. J. Leuk. Biol. 58, 90–98 (1995).

    Article  CAS  Google Scholar 

  19. Chisari, F.V. & Ferrari, C. Hepatitis B virus immunopathogenesis. Annu. Rev. Immunol. 13, 29–60 (1995).

    Article  CAS  Google Scholar 

  20. Kataoka, T. et al. Acidification is essential for maintaining the structure and function of lytic granules of CTL. J. Immunol. 153, 3938–3947 (1994).

    CAS  Google Scholar 

  21. Gavrieli, Y., Sherman, Y., St Ben-Sasson, S.A. Identification of programmed Cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–501 (1992).

    Article  CAS  Google Scholar 

  22. Adachi, M. et al. Targeted mutation in the Fas gene causes hyperplasia in the pe-ripheral lymphoid organs and liver. Nature Cenet. 11, 294–300 (1995).

    Article  CAS  Google Scholar 

  23. Hiramatsu, N. et al. Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology 19, 1354–1359 (1994).

    Article  CAS  Google Scholar 

  24. Vilanova, M. et al. Role of monocytes in the up-regulation of the early activation marker CD69 on B and T murine lymphocytes induced by microbial mitogens. Scand. J. Immunol. 43, 155–163 (1996).

    Article  CAS  Google Scholar 

  25. Kägi, D. et al. Cytotoxicity mediated by T Cells and natural killer Cells is greatly impaired in perforin-deficient mice. Nature 369, 31–37 (1994).

    Article  Google Scholar 

  26. Guidotti, L. et al. IntraCellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4, 25–36 (1996).

    Article  CAS  Google Scholar 

  27. Ellis, R.E., Yuan, J. & Horvitz, H.R. Mechanisms and functions of Cell death. Annu. Rev. Cell Biol. 7, 663–698 (1991).

    Article  CAS  Google Scholar 

  28. Ding, A., Nathan, C. & Stuehr, D. Release of reactive nitrogen intermediates and re active oxygen intermediates from mouse peritoneal macrophages. J. Immunol. 141, 2407–2412 (1988).

    CAS  PubMed  Google Scholar 

  29. Stuehr, D. & Marietta, M. Induction of nitrite/nitrate synthesis in murine macrophages by BCC infection, lymphokines or interferon-γ. J. Immunol. 139, 518–525 (1987).

    CAS  PubMed  Google Scholar 

  30. Tanaka, M. et al. Fas ligand in human serum. Nature Med. 2, 317–322 (1996).

    Article  CAS  Google Scholar 

  31. Enari, M., Hug, H., St Nagata, S. Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature 375, 78–81 (1995).

    Article  CAS  Google Scholar 

  32. Los, M. et al. Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apop-tosis. Nature 375, 81–83 (1995).

    Article  CAS  Google Scholar 

  33. Suda, T. & Nagata, S. Purification and characterization of the Fas ligand that in-duces apoptosis. J. Exp. Med. 179, 873–878 (1994).

    Article  CAS  Google Scholar 

  34. Torres, R.M. & Clark, E.A. Differential increase of an alternatively polyadenylated mRNA species of murine CD40 upon B lymphocyte activation. J. Immunol. 148, 620–626 (1992).

    CAS  PubMed  Google Scholar 

  35. Adachi, M. et al. Enhanced and accelerated lymphoproliferation in Fas-null mice. Proc. Natl. Acad. Sci. USA 93, 2137–2142 (1996).

    Article  Google Scholar 

  36. Ni, R. et al. Fas-mediated apoptosis in primary cultured mouse hepatocytes. Exp. Cell Res. 215, 332–337 (1994).

    Article  CAS  Google Scholar 

  37. Selgen, P.O. Preparation of isolated rat liver Cells. Methods Cell Biol. 13, 29–83 (1976).

    Article  Google Scholar 

  38. Takahashi, T. et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76, 969–976 (1994).

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka, 565, Japan

    Toru Kondo, Takashi Suda, Hidehiro Fukuyama, Masashi Adachi & Shigekazu Nagata

  2. Department of Genetics, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, 565, Japan

    Hidehiro Fukuyama

  3. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, 38101, USA

    Masashi Adachi

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  1. Toru Kondo
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  2. Takashi Suda
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  5. Shigekazu Nagata
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Kondo, T., Suda, T., Fukuyama, H. et al. Essential roles of the Fas ligand in the development of hepatitis. Nat Med 3, 409–413 (1997). https://doi.org/10.1038/nm0497-409

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