Gastroenterology
Volume 138, Issue 5 , Pages 1885-1897.e10, May 2010

Interferon-α–Induced TRAIL on Natural Killer Cells Is Associated With Control of Hepatitis C Virus Infection

  • Kerstin A. Stegmann

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    • ,
  • Niklas K. Björkström

      Affiliations

    • Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    • ,
  • Heike Veber

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Sandra Ciesek

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • Department of Experimental Virology, Twincore, Hannover, a joint venture between Hannover and the Helmholtz Centre for Infection Research, Braunschweig, Germany
    • ,
  • Peggy Riese

      Affiliations

    • Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
    • ,
  • Johannes Wiegand

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Johannes Hadem

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Pothakamuri V. Suneetha

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Jerzy Jaroszewicz

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Chun Wang

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Verena Schlaphoff

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Paraskevi Fytili

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Markus Cornberg

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Michael P. Manns

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Robert Geffers

      Affiliations

    • Division of Cell Biology and Immune Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
    • ,
  • Thomas Pietschmann

      Affiliations

    • Department of Experimental Virology, Twincore, Hannover, a joint venture between Hannover and the Helmholtz Centre for Infection Research, Braunschweig, Germany
    • ,
  • Carlos A. Guzmán

      Affiliations

    • Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
    • ,
  • Hans–Gustaf Ljunggren

      Affiliations

    • Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    • ,
  • Heiner Wedemeyer

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • Corresponding Author InformationReprint requests Address requests for reprints to: Professor Dr Heiner Wedemeyer, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. fax: (49) 511-532-6820

Received 22 April 2009; accepted 22 January 2010. published online 04 February 2010.

Background & Aims

Pegylated interferon-α (PEG-IFNα), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately 50% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, different immunomodulatory effects have been discussed. Natural killer (NK) cells might be associated with control of HCV infection. We examined the effects of IFNα on human NK cells and its relevance to HCV infection.

Methods

We performed gene expression profiling studies of NK cells following stimulation of peripheral blood mononuclear cells with IFNα. We evaluated IFNα-induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression using flow cytometry analyses of NK cells isolated from patients with acute or chronic hepatitis C that had received PEG-IFNα therapy.

Results

TRAIL was among the most up-regulated genes after IFNα stimulation of NK cells from healthy controls. After in vitro stimulation with IFNα, CD56dim NK cells from patients who had responded to PEG-IFNα therapy expressed higher levels of TRAIL than cells from patients with chronic hepatitis C. TRAIL expression, ex vivo, was inversely correlated with HCV-RNA levels during the early phase of PEG-IFNα therapy. In patients with acute hepatitis C, TRAIL expression on CD56bright NK cells increased significantly compared with cells from controls. In in vitro studies, IFNα-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism.

Conclusions

IFNα-induced expression of TRAIL on NK cells is associated with control of HCV infection; these observations might account for the second-phase decline in HCV-RNA levels during PEG-IFNα therapy.

Keywords: Hepatitis C, Interferon Alfa, TRAIL, NK Cells

Abbreviations used in this paper: NK, natural killer, PBMC, peripheral blood mononuclear cell, PEG–IFN-alfa, pegylated interferon-alfa, RT-PCR, reverse-transcription polymerase chain reaction, TNFSF10, tumor necrosis factor ligand superfamily member 10, TRAIL, tumor necrosis factor-related apoptosis-inducing ligand

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 View this article's video abstract at www.gastrojournal.org.

 Conflicts of interest These authors disclose the following: Heiner Wedemeyer, Michael Manns, Markus Cornberg, and Johannes Wiegand have received lecturer fees and research funding from several companies involved in treating viral hepatitis C including Roche and Schering-Plough. The remaining authors disclose no conflicts.

 Funding This study was funded by the International Research Training Group 1273 funded by the German Research Foundation (DFG), the SFB center grant 738 (Project B2) funded by the DFG, a grant from the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative (M.P.M. and H.W.), and the Bundesministerium für Bildung und Forschung grant 01Kl0788 (H.W. and M.C.).

 The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus (accession number GSE15743, available: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15743).

PII: S0016-5085(10)00160-5

doi:10.1053/j.gastro.2010.01.051

Gastroenterology
Volume 138, Issue 5 , Pages 1885-1897.e10, May 2010

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