title: Acetaldehyde accelerates HCV-induced impairment of innate immunity by suppressing methylation reactions in liver cells.
abstract: Alcohol exposure worsens the course and outcomes of hepatitis C virus (HCV) infection. Activation of protective antiviral genes is induced by IFN-α signaling, which is altered in liver cells by either HCV or ethanol exposure. However, the mechanisms of the combined effects of HCV and ethanol metabolism in IFN-α signaling modulation are not well elucidated. Here, we explored a possibility that ethanol metabolism potentiates HCV-mediated dysregulation of IFN-α signaling in liver cells via impairment of methylation reactions. HCV-infected Huh7.5 CYP2E1(+) cells and human hepatocytes were exposed to acetaldehyde (Ach)-generating system (AGS) and stimulated with IFN-α to activate IFN-sensitive genes (ISG) via the Jak-STAT-1 pathway. We observed significant suppression of signaling events by Ach. Ach exposure decreased STAT-1 methylation via activation of protein phosphatase 2A and increased the protein inhibitor of activated STAT-1 (PIAS-1)-STAT-1 complex formation in both HCV(+) and HCV(-) cells, preventing ISG activation. Treatment with a promethylating agent, betaine, attenuated all examined Ach-induced defects. Ethanol metabolism-induced changes in ISGs are methylation related and confirmed by in vivo studies on HCV(+) transgenic mice. HCV- and Ach-induced impairment of IFN signaling temporarily increased HCV RNA levels followed by apoptosis of heavily infected cells. We concluded that Ach potentiates the suppressive effects of HCV on activation of ISGs attributable to methylation-dependent dysregulation of IFN-α signaling. A temporary increase in HCV RNA sensitizes the liver cells to Ach-induced apoptosis. Betaine reverses the inhibitory effects of Ach on IFN signaling and thus can be used for treatment of HCV(+) alcohol-abusing patients.
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Murali
authors.initials: M
authors.lastname: Ganesan
authors.affiliation: School of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Jinjin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Tatiana
authors.initials: T
authors.lastname: Bronich
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Pharmacology and Experimental Neuroscience, Omaha, Nebraska.
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Poluektova
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Donohue
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tuma
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Kusum K
authors.initials: KK
authors.lastname: Kharbanda
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; nosna@unmc.edu.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Osna
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology*; D000818:Animals; D001622:Betaine / Q000494:pharmacology; D002460:Cell Line; D019175:DNA Methylation / Q000187:drug effects*; D000431:Ethanol / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D015151:Immunoblotting; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D000431:Ethanol; D001622:Betaine; D000079:Acetaldehyde
keywords: IFN-α signaling; betaine; ethanol metabolism; hepatitis C virus; hepatocytes