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.
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Haizhen
H
Zhu
Xianzhang
X
Shang
Naohiro
N
Terada
Chen
C
Liu
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