Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection

Gastroenterology. 2010 May;138(5):1885-97. doi: 10.1053/j.gastro.2010.01.051. Epub 2010 Feb 2.

Abstract

Background & aims: Pegylated interferon-alpha (PEG-IFNalpha), 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 IFNalpha 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 IFNalpha. We evaluated IFNalpha-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-IFNalpha therapy.

Results: TRAIL was among the most up-regulated genes after IFNalpha stimulation of NK cells from healthy controls. After in vitro stimulation with IFNalpha, CD56(dim) NK cells from patients who had responded to PEG-IFNalpha 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-IFNalpha therapy. In patients with acute hepatitis C, TRAIL expression on CD56(bright) NK cells increased significantly compared with cells from controls. In in vitro studies, IFNalpha-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism.

Conclusions: IFNalpha-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-IFNalpha therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use*
  • CD56 Antigen / analysis
  • Cell Line, Tumor
  • Coculture Techniques
  • Cytotoxicity, Immunologic / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Profiling
  • Hepacivirus / drug effects
  • Hepacivirus / genetics
  • Hepacivirus / pathogenicity
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / genetics
  • Hepatitis C, Chronic / immunology
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / therapeutic use*
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Polyethylene Glycols / therapeutic use*
  • RNA, Viral / blood
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Time Factors
  • Treatment Outcome
  • Up-Regulation
  • Viral Load
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • CD56 Antigen
  • Interferon alpha-2
  • Interferon-alpha
  • RNA, Viral
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Polyethylene Glycols
  • peginterferon alfa-2b
  • peginterferon alfa-2a

Associated data

  • GENBANK/GSE15743