STAT3 induces anti-hepatitis C viral activity in liver cells.
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.
Zhu
Haizhen
H
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Shang
Xianzhang
X
Terada
Naohiro
N
Liu
Chen
C
D000998:Antiviral Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D016174:Hepacivirus / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007372:Interferons / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000821:virology*; D008113:Liver Neoplasms / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
D000998:Antiviral Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008024:Ligands; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D012254:Ribavirin; D012313:RNA; D007372:Interferons; D008156:Luciferases