These authors contributed equally.
Article first published online: 14 NOV 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 1, pages 39–48, January 2012
How to Cite
Edlich, B., Ahlenstiel, G., Zabaleta, A. A., Stoltzfus, J., Noureddin, M., Serti, E., Feld, J. J., Liang, T. J., Rotman, Y. and Rehermann, B. (2012), Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients. Hepatology, 55: 39–48. doi: 10.1002/hep.24628
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.
- Issue published online: 21 DEC 2011
- Article first published online: 14 NOV 2011
- Accepted manuscript online: 24 AUG 2011 01:53PM EST
- Manuscript Accepted: AUG 2011
- Manuscript Received: 8 JUN 2011
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)