title: 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.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.forename: Gaia
authors.initials: G
authors.lastname: Trincucci
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Gruber
authors.forename: Julia E
authors.initials: JE
authors.lastname: Vogt
authors.forename: Magdalena
authors.initials: M
authors.lastname: Filipowicz
authors.forename: Diego
authors.initials: D
authors.lastname: Calabrese
authors.forename: Ilona
authors.initials: I
authors.lastname: Krol
authors.forename: Daryl T
authors.initials: DT
authors.lastname: Lau
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Erik
authors.initials: E
authors.lastname: van Nimwegen
authors.forename: Volker
authors.initials: V
authors.lastname: Roth
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D000077190:Interferon alpha-2; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase
chemical_list: D000998:Antiviral Agents; C494227:IRF9 protein, human; D000077190:Interferon alpha-2; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D011994:Recombinant Proteins; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011092:Polyethylene Glycols; D053612:Janus Kinases; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase; C417083:peginterferon alfa-2b