STAT3 induces anti-hepatitis C viral activity in liver cells

Biochem Biophys Res Commun. 2004 Nov 12;324(2):518-28. doi: 10.1016/j.bbrc.2004.09.081.


Hepatitis C virus (HCV) infection is a leading cause a of chronic liver disease worldwide. The main therapeutic regimen is the combination of interferon alpha (IFN) and the nucleoside analog, Ribavirin. IFN initiates an intracellular antiviral state by the JAK-STAT signaling pathway, including a presumed role for STAT1 and STAT2. We have previously shown that the STAT3 activation occurs during IFN treatment of human hepatoma cells, suggesting that the STAT3-mediated pathway is relevant to IFN-induced antiviral activity. In this study, we investigate the role of activated STAT3 in the induction of anti-HCV activity in human hepatoma cells. We demonstrate that the STAT3 activation is involved in efficient IFN-induced anti-HCV activity. Using an inducible, cytokine-independent, STAT3 activation system, in which the entire coding region of STAT3 is fused with the ligand-binding domain of the estrogen receptor, we demonstrate that: activated STAT3 is tightly regulated in a stably transfected cell line by an estrogen analog, 4-HT; activated STAT3 initiates efficient anti-HCV activity in a HCV subgenomic replicon cell line; and activation of STAT3 is associated with the induction of a potential antiviral gene, 1-8U. In addition, we show that the cytokine IL-6, a potent STAT3 activator, inhibits HCV subgenomic RNA replication through STAT3 activation and ERK pathway. These results strongly suggest that STAT3 activation is capable of initiating intracellular antiviral pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antiviral Agents / pharmacology
  • Blotting, Northern
  • Blotting, Western
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Genes, Dominant
  • Hepacivirus / genetics*
  • Hepacivirus / metabolism
  • Humans
  • Inflammation
  • Interferons / metabolism
  • Interleukin-6 / metabolism
  • Ligands
  • Liver / virology*
  • Liver Neoplasms / metabolism
  • Luciferases / metabolism
  • Plasmids / metabolism
  • Protein Structure, Tertiary
  • RNA / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribavirin / pharmacology
  • STAT3 Transcription Factor
  • Time Factors
  • Trans-Activators / metabolism*
  • Transfection
  • Tyrphostins / pharmacology


  • Antiviral Agents
  • Cytokines
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Interleukin-6
  • Ligands
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Ribavirin
  • RNA
  • Interferons
  • Luciferases