Interferon-γ inhibits interferon-α signalling in hepatic cells: Evidence for the involvement of STAT1 induction and hyperexpresslon of STAT1 in chronic hepatitis C

Svetlana Radaeva, Barbara Jaruga, Won Ho Kim, Theo Heller, T. Jake Liang, Bin Gao

Research output: Contribution to journalArticle

Abstract

IFN-γ (Interferon-γ) modulates IFN-α therapy in chronic hepatitis C infection; however, the underlying mechanism remains unclear. Here we demonstrate that long-term (3-6 days) but not short-term (up to 1 day) IFN-γ treatment of human hepatoma Hep3B cells attenuates IFN-α activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3, but enhances IFN-γ and interleukin 6 activation of STATs. Prolonged exposure to IFN-γ also significantly induces STAT1 protein expression without affecting STAT2, STAT3 and ERK (extracellular-signal- regulated kinase) 1/2 protein expression. To determine the role of STAT1 protein overexpression in regulation of IFN-α signalling, Hep3B cells were stably transfected with wild-type STAT1. Overexpression of STAT1 via stable transfection enhances IFN-γ activation of STAT1, but surprisingly attenuates IFN-α activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation. This STAT1-mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant-negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-α activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-α-activated STAT2 translocation from IFN-α receptor 2 to IFN-α receptor 1, a critical step in IFN-α signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-γ, are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-γ treatment inhibits IFN-α-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-α treatment failure in hepatitis C patients.

Original languageEnglish (US)
Pages (from-to)199-208
Number of pages10
JournalBiochemical Journal
Volume379
Issue number1
DOIs
Publication statusPublished - Apr 1 2004
Externally publishedYes

    Fingerprint

Keywords

  • Hep3B
  • Hepatitis
  • Interferon (IFN)
  • Liver
  • Signal transducers and activators of transcription factor (STAT)

ASJC Scopus subject areas

  • Biochemistry

Cite this