Increased hepatotoxicity of tumor necrosis factor–related apoptosis-inducing ligand in diseased human liver

Authors

  • Xandra Volkmann,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Ute Fischer,

    1. Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany
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  • Matthias J. Bahr,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Michael Ott,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Frank Lehner,

    1. Department of Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
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  • Marion MacFarlane,

    1. Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom
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  • Gerald M. Cohen,

    1. Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom
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  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Klaus Schulze-Osthoff,

    Corresponding author
    1. Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany
    • Klaus Schulze-Osthoff, University of Düsseldorf, Institute of Molecular Medicine, Universitätsstrasse 1, D-40225 Düsseldorf, Germany===

      Heike Bantel, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany===

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    • fax: (49) 211-8115892

  • Heike Bantel

    Corresponding author
    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • Klaus Schulze-Osthoff, University of Düsseldorf, Institute of Molecular Medicine, Universitätsstrasse 1, D-40225 Düsseldorf, Germany===

      Heike Bantel, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany===

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    • fax: (49) 511-5326998


  • Potential conflict of interest: Nothing to report.

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases. (HEPATOLOGY 2007.)

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