Interferon-γ-stimulated genes, but not USP18, are expressed in livers of patients with acute hepatitis C.
Gastroenterology, 2012/9;143(3):777-786.e6.
Dill MT[1], Makowska Z[2], Duong FHT[2], Merkofer F[2], Filipowicz M[2], Baumert TF[3], Tornillo L[4], Terracciano L[4], Heim MH[5]
Affiliations
PMID: 22677194DOI: 10.1053/j.gastro.2012.05.044
Impact factor: 33.883
Abstract
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.
MeSH terms
Acute Disease; Adolescent; Adult; Antiviral Agents; Biopsy; Blotting, Western; CD8-Positive T-Lymphocytes; Cells, Cultured; Drug Resistance, Viral; Drug Therapy, Combination; Endopeptidases; Female; Gene Expression Profiling; Gene Expression Regulation; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Host-Pathogen Interactions; Humans; Immunohistochemistry; Interferon-alpha; Interferon-gamma; Liver; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Phosphorylation; Polyethylene Glycols; Recombinant Proteins; Ribavirin; STAT1 Transcription Factor; Switzerland; Time Factors; Transcription, Genetic; Treatment Outcome; Ubiquitin Thiolesterase
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