Interferon-γ-stimulated genes, but not USP18, are expressed in livers of patients with acute hepatitis C

Gastroenterology. 2012 Sep;143(3):777-786.e6. doi: 10.1053/j.gastro.2012.05.044. Epub 2012 Jun 4.


Background & aims: Approximately 50% of patients with chronic hepatitis C (CHC) have a sustained virologic response to treatment with pegylated interferon (pegIFN)-α and ribavirin. Nonresponse to treatment is associated with constitutively increased expression of IFN-stimulated genes (ISGs) in the liver. Treatment of patients with acute hepatitis C (AHC) is more effective, with sustained virologic response rates greater than 90%. We investigated mechanisms of the different responses of patients with CHC and AHC to pegIFN-α therapy.

Methods: We analyzed IFN signaling and ISG expression in liver samples from patients with AHC, patients with CHC, and individuals without hepatitis C (controls) using microarray, immunohistochemical, and protein analyses. Findings were compared with those from primary human hepatocytes stimulated with IFN-α or IFN-γ, as reference sets.

Results: Expression levels of hundreds of genes, primarily those regulated by IFN-γ, were altered in liver samples from patients with AHC compared with controls. Expression of IFN-γ-stimulated genes was induced in liver samples from patients with AHC, whereas expression of IFN-α-stimulated genes was induced in samples from patients with CHC. In an expression analysis of negative regulators of IFN-α signaling, we did not observe differences in expression of suppresor of cytokine signaling 1 or SOCS3 between liver samples from patients with AHC and those with CHC. However, USP18 (another negative regulator of IFN-α signaling), was up-regulated in liver samples of patients with CHC that did not respond to therapy, but not in AHC.

Conclusions: Differences in expression of ISGs might account for the greater response of patients with AHC, compared with those with CHC, to treatment with pegIFN-α and ribavirin. Specifically, USP18 is up-regulated in liver samples of patients with CHC that did not respond to therapy, but not in patients with AHC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Antiviral Agents / therapeutic use*
  • Biopsy
  • Blotting, Western
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Drug Resistance, Viral / genetics
  • Drug Therapy, Combination
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation
  • Hepacivirus / pathogenicity
  • Hepatitis C / diagnosis
  • Hepatitis C / drug therapy*
  • Hepatitis C / genetics
  • Hepatitis C / metabolism
  • Hepatitis C, Chronic / diagnosis
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / genetics
  • Hepatitis C, Chronic / metabolism
  • Host-Pathogen Interactions
  • Humans
  • Immunohistochemistry
  • Interferon-alpha / therapeutic use*
  • Interferon-gamma / metabolism*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver / virology
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Polyethylene Glycols / therapeutic use*
  • Recombinant Proteins / therapeutic use
  • Ribavirin / therapeutic use*
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Switzerland
  • Time Factors
  • Transcription, Genetic
  • Treatment Outcome
  • Ubiquitin Thiolesterase


  • Antiviral Agents
  • Interferon-alpha
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Polyethylene Glycols
  • Ribavirin
  • Interferon-gamma
  • Endopeptidases
  • USP18 protein, human
  • Ubiquitin Thiolesterase
  • peginterferon alfa-2a