HBsAg retention sensitizes the hepatocyte to injury by physiological concentrations of interferon-γ

Authors

  • Patrick N. Gilles,

    1. The Departments of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
    Current affiliation:
    1. Department of Pediatrics, Division of Infectious Diseases, School of Medicine, Mail Code 0672, University of California at San Diego, La Jolla, CA 92093
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  • Deborah L. Guerrette,

    1. The Departments of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
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  • Richard J. Ulevitch,

    1. The Departments of Immunology, The Scripps Research Institute, La Jolla, California 92037
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  • Robert D. Schreiber,

    1. The Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
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  • Francis V. Chisari

    Corresponding author
    1. The Departments of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
    • Department of Molecular and Experimental Medicine, BCR-10, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037
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Abstract

The role that inflammatory cytokines may play in the life cycle of the hepatitis B virus and in the pathogenesis of its associated liver disease has not been carefully delineated. In this report, we demonstrate that bacterial lipopolysaccharide, a potent inducer of inflammatory cytokines in vivo, causes a severe acute liver disease in transgenic mice whose hepatocytes produce the hepatitis B virus large envelope polypeptide and retain HBsAg within the endoplasmic reticulum. In contrast, 100-fold higher doses of bacterial lipopolysaccharide do not induce liver cell injury in nontransgenic littermate controls or in transgenic mice whose hepatocytes secrete HBsAg rather than retain it. Coincident with the hepatocellular injury and the influx of inflammatory cells into the liver, a marked reduction occurs in the intrahepatic content of hepatitis B virus steady-state messenger RNA, thereby confirming the selectivity of this process for the HBsAg-positive hepatocyte. Bacterial lipopolysaccharide-induced hepatocellular injury appears to be principally mediated by interferon-γ because it can be markedly reduced by the prior administration of neutralizing interferon-γ–specific monoclonal antibodies and because recombinant interferon-γ is also selectively cytotoxic for the HBsAg-positive transgenic hepatocyte in vivo. Tumor necrosis factor–α is also involved in this process because bacterial lipopolysaccharide-induced liver cell injury is significantly reduced by tumor necrosis factor–α specific monoclonal antibodies. The role of tumor necrosis factor–α in bacterial lipopolysaccharide–induced liver cell injury is less clear than interferon-γ, however, because unlike interferon-γ it is also toxic for nontransgenic hepatocytes. These results demonstrate that the HBsAg-positive transgenic mouse hepatocyte is selectively sensitive to destruction by interferon-γ in vivo. Because this cytokine has been shown to be produced by intrahepatic lymphocytes during viral hepatitis in humans, these results raise the possibility that a similar pathway may contribute to the clearance of HBsAg-positive hepatocytes and to the pathogenesis of liver cell injury in human HBV infection as well. (HEPATOLOGY 1992;16:655–663.)

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