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

ABSTRACT: The use of pegylated interferon-? (pegIFN-?) has replaced unmodified recombinant IFN-? for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-? is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-? in the liver have not been studied. Here, we analyzed pegIFN-?-induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-? injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-? in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-? administration. Evaluation of liver biopsies revealed that pegIFN-? 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-? therapy, pegIFN-? 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-? 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.

SUBMITTER: Dill MT

PROVIDER: S-EPMC3973080 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Dill Michael T MT Makowska Zuzanna Z Trincucci Gaia G Gruber Andreas J AJ Vogt Julia E JE Filipowicz Magdalena M Calabrese Diego D Krol Ilona I Lau Daryl T DT Terracciano Luigi L van Nimwegen Erik E Roth Volker V Heim Markus H MH

The Journal of clinical investigation 20140224 4

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 1 ...[more]

PMID: 24569457

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

Publications

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

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