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Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation
Michael T. Dill, … , Volker Roth, Markus H. Heim
Michael T. Dill, … , Volker Roth, Markus H. Heim
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(4):1568-1581. https://doi.org/10.1172/JCI70408.
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Research Article Immunology Article has an altmetric score of 11

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

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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.

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 8

Late ISGs show a more prolonged transcriptional induction and a slower mRNA degradation rate than early ISGs in vitro.

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Late ISGs show a more prolonged transcriptional induction and a slower m...
(A) mRNA degradation of early (RSAD2, USP18) and late (IFI27, LGALS3BP) ISGs was assessed in Huh7 after induction with 1,000 U/ml of IFN-α for 6 hours at the indicated time points. Transcription was blocked with actinomycin D, and the mRNA degradation over time was compared with GAPDH by qRT-PCR. Results from two independent experiments run in duplicate are shown. (B) Transcription rates of early (RSAD2, USP18) and late (IFI27, LGALS3BP) ISGs over time in Huh7 cells treated with 1,000 U/ml of IFN-α for the indicated time points. In vitro transcription in isolated nuclei was performed for 45 minutes. Newly transcribed mRNA labeled with biotinylated UTP was isolated and assessed by qRT-PCR. Results depicted as relative transcription compared with untreated baseline are shown from two independent experiments run in duplicate.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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