Acrolein, a ubiquitous pollutant and lipid hydroperoxide product, inhibits antiviral activity of interferon-alpha: relevance to hepatitis C.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and can lead to hepatocellular carcinoma and end-stage liver disease. The current FDA-approved treatment for HCV (pegylated interferon-alpha (IFNalpha) with ribavirin) is effective in only about 50% of patients. Epidemiological evidence suggests that obesity, alcohol, smoking, and environmental pollutants may contribute to resistance to IFNalpha therapy in HCV. Acrolein, a ubiquitous environmental pollutant and major component of cigarette smoke, is also generated endogenously by cellular metabolism and lipid peroxidation. This study examines the effects of acrolein on (i) IFNalpha-mediated signaling and antiviral gene expression in cultured and primary human hepatocytes and (ii) HCV replication in an HCV-replicon system. Our data demonstrate that nontoxic concentrations of acrolein significantly inhibited IFNalpha-induced tyrosine phosphorylation of both cytoplasmic and nuclear STAT1 and STAT2, without altering the total levels. Also, acrolein down-regulated IFNalpha-stimulated gene transcription, resulting in reduced expression of antiviral genes. Importantly, acrolein abolished the IFNalpha-mediated down-regulation of HCV viral expression in the HCV-replicon system. This study defines mechanisms involved in resistance to IFNalpha and identifies the pathogenic role of acrolein, and potentially other environmental pollutants, in suppressing IFNalpha antiviral activity and establishes their adverse impact on HCV therapy.
Joshi-Barve
Swati
S
Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA.
Amancherla
Kiranmayi
K
Patil
Madhuvanti
M
Bhatnagar
Aruni
A
Mathews
Stephanie
S
Gobejishvili
Leila
L
Cave
Matthew
M
McClain
Craig
C
Barve
Shirish
S
D000171:Acrolein / Q000276:immunology / Q000378:metabolism*; D000393:Air Pollutants / Q000276:immunology / Q000378:metabolism*; D000998:Antiviral Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D015536:Down-Regulation; D024882:Drug Resistance, Viral; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use*; D015227:Lipid Peroxidation; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins; D012093:Replicon; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking; D014481:United States; D014486:United States Food and Drug Administration; D014774:Virulence; D014779:Virus Replication
D000393:Air Pollutants; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D011092:Polyethylene Glycols; D000171:Acrolein; C100416:peginterferon alfa-2a