Alcohol impairs interferon signaling and enhances full cycle hepatitis C virus JFH-1 infection of human hepatocytes.
Alcohol drinking and hepatitis C virus (HCV) infection frequently coexist in patients with chronic liver disease. There is limited information, however, about the impact of alcohol on host cell innate immunity and full cycle replication of HCV. This study investigated whether alcohol impairs the intracellular innate immunity in human hepatocytes, promoting HCV infection and replication. Alcohol treatment of human hepatocytes before, during and after viral infection significantly enhanced full cycle HCV replication. Alcohol suppressed intracellular expression of type I interferons (IFN-α/β) in human hepatocytes. Investigation of the mechanisms responsible for the alcohol action revealed that alcohol inhibited the expression of the IFN regulatory factors (IRF-5 and IRF-7), and signal transducer and activator of transcription (STAT-1 and STAT-2), the key positive regulators in type I IFN signaling pathway. In addition, alcohol induced the expression of suppressors of cytokine signaling (SOCS-2 and SOCS-3), the key negative regulators of IFN-α/β expression. These in vitro findings suggest that alcohol, through modulating the expression of key regulators in IFN signaling pathway, inhibits type I IFN-based intracellular innate immunity in hepatocytes, which may contribute to the chronicity of HCV infection and the poor efficacy of IFN-α-based therapy.
Ye
Li
L
Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Wang
Shihong
S
Wang
Xu
X
Zhou
Yu
Y
Li
Jieliang
J
Persidsky
Yuri
Y
Ho
Wenzhe
W
D000428:Alcohol Drinking / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology*; D016174:Hepacivirus / Q000276:immunology / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014779:Virus Replication
C431713:IRF5 protein, human; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000431:Ethanol; D016899:Interferon-beta