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Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients

Authors

  • Birgit Edlich,

    1. Immunology Section, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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    • These authors contributed equally.

  • Golo Ahlenstiel,

    1. Immunology Section, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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    • These authors contributed equally.

  • Aintzane Azpiroz Zabaleta,

    1. Immunology Section, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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  • Jonathan Stoltzfus,

    1. Immunology Section, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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  • Mazen Noureddin,

    1. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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  • Elisavet Serti,

    1. Immunology Section, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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  • Jordan J. Feld,

    1. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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  • T. Jake Liang,

    1. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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  • Yaron Rotman,

    1. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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  • Barbara Rehermann

    Corresponding author
    1. Immunology Section, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    • Immunology Section, Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, 10 Center Drive, Building 10, Room 9B16, Bethesda, MD 20892
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    • fax: 301-402-0491


  • Potential conflict of interest: Nothing to report.

  • This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program.

Abstract

Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased interferon gamma (IFN-γ) production in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is caused by type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-α-based therapy of HCV. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-α-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (tumor necrosis factor–apoptosis-inducing ligand [TRAIL] expression and degranulation) and decreased IFN-γ production. NK cells from patients with a greater than 2 log10 first-phase HCV RNA decline to IFN-α-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log10 first-phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (P = 0.024), but retained greater IFN-α responsiveness in vitro (P = 0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-α during the second-phase virological response. Conclusion: These data show that IFN-α-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells toward increased cytotoxicity and decreased IFN-γ production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-α-based therapy. (Hepatology 2012)

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