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

Dill, Michael T. and Makowska, Zuzanna and Trincucci, Gaia and Gruber, Andreas J. and Vogt, Julia E. and Filipowicz, Magdalena and Calabrese, Diego and Krol, Ilona and Lau, Daryl T. and Terracciano, Luigi and van Nimwegen, Erik and Roth, Volker and Heim, Markus H.. (2014) Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation. Journal of Clinical Investigation, Vol. 124, H. 4. pp. 1568-1581.

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Official URL: http://edoc.unibas.ch/dok/A6243443

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (van Nimwegen)
05 Faculty of Science > Departement Mathematik und Informatik > Informatik > Datenanalyse (Roth)
UniBasel Contributors:Roth, Volker and Heim, Markus H. and van Nimwegen, Erik and Terracciano, Luigi M. and Gruber, Andreas J.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
e-ISSN:1558-8238
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Oct 2017 08:21
Deposited On:23 May 2014 08:33

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