Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation
Michael T. Dill, Zuzanna Makowska, Gaia Trincucci, Andreas J. Gruber, Julia E. Vogt, Magdalena Filipowicz, Diego Calabrese, Ilona Krol, Daryl T. Lau, Luigi Terracciano, Erik van Nimwegen, Volker Roth, Markus H. Heim
Michael T. Dill, Zuzanna Makowska, Gaia Trincucci, Andreas J. Gruber, Julia E. Vogt, Magdalena Filipowicz, Diego Calabrese, Ilona Krol, Daryl T. Lau, Luigi Terracciano, Erik van Nimwegen, Volker Roth, Markus H. Heim
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Research Article Immunology

Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation

Abstract

The use of pegylated interferon-α (pegIFN-α) has replaced unmodified recombinant IFN-α for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-α is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-α in the liver have not been studied. Here, we analyzed pegIFN-α–induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-α injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-α in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-α administration. Evaluation of liver biopsies revealed that pegIFN-α induces hundreds of genes that can be classified into four clusters based on different temporal expression profiles. In all clusters, gene transcription was mainly driven by IFN-stimulated gene factor 3 (ISGF3). Compared with conventional IFN-α therapy, pegIFN-α induced a broader spectrum of gene expression, including many genes involved in cellular immunity. IFN-induced secondary transcription factors did not result in additional waves of gene expression. Our data indicate that the superior antiviral efficacy of pegIFN-α is not the result of prolonged Jak/STAT pathway activation in hepatocytes, but rather is due to induction of additional genes that are involved in cellular immune responses.

Authors

Michael T. Dill, Zuzanna Makowska, Gaia Trincucci, Andreas J. Gruber, Julia E. Vogt, Magdalena Filipowicz, Diego Calabrese, Ilona Krol, Daryl T. Lau, Luigi Terracciano, Erik van Nimwegen, Volker Roth, Markus H. Heim

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Figure 3

The negative regulator USP18 is continuously upregulated during the entire week after pegIFN-α2b injection.

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The negative regulator USP18 is continuously upregulated during the enti...
(A) Bar plot indicating the mRNA expression fold change between the pretreatment biopsy (B1) and the on-treatment biopsy (B2) of SOCS1, SOCS3, and USP18. Data represent the mean with SEM (n = 6 for the 4-hour time point; n = 3 for all other time points). The black line indicates the baseline measured in pretreatment biopsies from the same patients (n = 18). (B) USP18 protein expression by Western blot analysis using whole-cell extracts of liver samples from B1 and B2. Patients are numbered according to Table 1. (C) Representative images of IHC for USP18 of liver biopsies obtained before treatment (B1) and at several time points after the first injection of pegIFN-α2b as indicated. Scale bars: 20 μm.