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

Academic Article
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Overview

authors

  • Gilles, P. N.
  • Guerrette, D. L.
  • Ulevitch, Richard
  • Schreiber, R. D.
  • Chisari, Francis

publication date

  • September 1992

journal

  • Hepatology  Journal

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-gamma because it can be markedly reduced by the prior administration of neutralizing interferon-gamma-specific monoclonal antibodies and because recombinant interferon-gamma is also selectively cytotoxic for the HBsAg-positive transgenic hepatocyte in vivo. Tumor necrosis factor-alpha is also involved in this process because bacterial lipopolysaccharide-induced liver cell injury is significantly reduced by tumor necrosis factor-alpha specific monoclonal antibodies. The role of tumor necrosis factor-alpha in bacterial lipopolysaccharide-induced liver cell injury is less clear than interferon-gamma, however, because unlike interferon-gamma it is also toxic for nontransgenic hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

subject areas

  • Alanine Transaminase
  • Animals
  • Biopsy
  • Cell Death
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum
  • Hepatitis B
  • Hepatitis B Surface Antigens
  • Immunity, Cellular
  • Interferon-gamma
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • Liver
  • Mice
  • Mice, Transgenic
  • RNA, Messenger
  • Recombinant Proteins
  • Species Specificity
  • Time Factors
  • Tumor Necrosis Factor-alpha
  • Zinc
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Identity

International Standard Serial Number (ISSN)

  • 0270-9139

Digital Object Identifier (DOI)

  • 10.1002/hep.1840160308

PubMed ID

  • 1505908
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Additional Document Info

start page

  • 655

end page

  • 663

volume

  • 16

issue

  • 3

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