Interferon-γ-stimulated genes, but not USP18, are expressed in livers of patients with acute hepatitis C.
OBJECTIVE
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.
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
Michael T
MT
Dill
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Zuzanna
Z
Makowska
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Francois H T
FHT
Duong
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Franzisca
F
Merkofer
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Magdalena
M
Filipowicz
Inserm, U748, University of Strasbourg, Strasbourg, France.
Thomas F
TF
Baumert
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Luigi
L
Tornillo
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Luigi
L
Terracciano
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland. Electronic address: markus.heim@unibas.ch.
Markus H
MH
Heim
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001706:Biopsy; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000472:pathogenicity; D006526:Hepatitis C / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013557:Switzerland; D013997:Time Factors; D014158:Transcription, Genetic; D016896:Treatment Outcome; D043222:Ubiquitin Thiolesterase
D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D011092:Polyethylene Glycols; D012254:Ribavirin; D007371:Interferon-gamma; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase; C100416:peginterferon alfa-2a