Gastroenterology

Gastroenterology

Volume 143, Issue 3, September 2012, Pages 777-786.e6
Gastroenterology

Original Research
Basic and Translational—Liver
Interferon-γ–Stimulated Genes, but Not USP18, Are Expressed in Livers of Patients With Acute Hepatitis C

https://doi.org/10.1053/j.gastro.2012.05.044Get rights and content

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.

Section snippets

Patients

All patients were recruited in the Hepatology Outpatient Clinic of the University Hospital Basel (Basel, Switzerland). From October 2007 to December 2010, 6 patients with AHC (between 0 and 6 months after the HCV transmission) gave written informed consent to participate in this study and donated a liver biopsy specimen for research purposes. The study was approved by the Ethics Committee of Basel.

Liver biopsy specimens from 16 patients with CHC and 4 normal liver tissue samples were used for

Host–Virus Interactions During Acute Hepatitis C Induce a Distinct Pattern of Gene Expression in the Liver

Six patients with HCV monoinfection underwent a liver biopsy 2–5 months after HCV transmission (ie, during the acute phase of HCV infection) (Table 1). Gene expression in these liver biopsy specimens was analyzed with Affymetrix U133 Plus 2.0 arrays and compared with 4 samples from patients without liver disease (controls) and 16 samples from patients with CHC recruited in a previous study.7 We found between 203 and 492 genes (average, 312) up-regulated and 239 to 374 genes (average, 294)

Discussion

The study of the acute phase of HCV infection in human beings is hampered by the fact that most cases are asymptomatic. Spontaneous clearance occurs in about 20%–30% of patients.25 Studies of subjects after needlestick injuries revealed a very rapid increase of HCV viral load to maximal levels within the first 2–4 weeks.20 Viral replication then is slowed down, most likely by an innate immune response involving the induction of ISGs in the liver.14, 19 HCV-specific T cells are detectable 5–9

Acknowledgments

The authors thank the patients who participated in this study. The authors are grateful to Tanja Dietsche for excellent technical assistance with immunohistochemistry, Philippe Demougin (Life Sciences Training Facility, Pharmazentrum, Basel, Switzerland) for providing technical help with the processing of microarrays, and Sarah Durand and Cathy Royer (Inserm U748) for isolation and culture of primary human hepatocytes.

References (33)

  • M. Sarasin-Filipowicz et al.

    Interferon signaling and treatment outcome in chronic hepatitis C

    Proc Natl Acad Sci U S A

    (2008)
  • T. Asselah et al.

    Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C

    Gut

    (2008)
  • M. Sarasin-Filipowicz et al.

    Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43

    Mol Cell Biol

    (2009)
  • E. Jaeckel et al.

    Treatment of acute hepatitis C with interferon alfa-2b

    N Engl J Med

    (2001)
  • J. Wiegand et al.

    Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study

    Hepatology

    (2006)
  • C.B. Bigger et al.

    DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection

    J Virol

    (2001)
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      Citation Excerpt :

      Third, IFNα cannot be the driver of ISG expression because IFNα signaling is refractory in these patients [29,30]. Refractoriness or non-response to IFNα is most likely caused by USP18, a classical ISG itself and a strong inhibitor of IFNα receptor signaling that is highly expressed in the liver of patients with CHC and high ISG expression [19,31,32]. During the 25 years of (Peg)IFNα based treatments for CHC, the clinical consequence of this refractoriness was non-response to treatment (reviewed in [33]).

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    M.T.D. and Z.M. contributed equally to this work.

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by Swiss National Science Foundation grants 320030_130243 (M.H.H.) and 323500-123714 (M.T.D.).

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