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Environmental pollutant and lipid peroxidation product, acrolein, inhibits interferon‐alpha mediated antiviral signaling in human hepatocytes: relevance for HCV therapy
Author(s) -
JoshiBarve Swati,
Amancherla Kiranmayi,
Patil Madhuvanti,
Bhatnagar Aruni,
Srivastava Sanjay,
Gobejishvili Leila,
McClain Craig,
Barve Shirish
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.646.10
Subject(s) - oxidative stress , lipid peroxidation , tyrosine phosphorylation , signal transduction , medicine , chemistry , cancer research , biochemistry
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease in the US and is a precursor to cirrhosis, end‐stage liver disease, hepatocellular carcinoma and death. The FDA approved standard of care for chronic hepatitis C, is pegylated interferon‐alpha (IFNα) combined with ribavirin which is effective only in about 50% of patients. Studies have identified potential cofactors that contribute to the failure of anti‐HCV therapy, including obesity, elevated lipid peroxidation, oxidative stress and environmental pollutants. Acrolein (ACR), a highly reactive aldehyde, is formed endogenously through cellular lipid peroxidation and is also a common, ubiquitous environmental pollutant. Exposure to ACR induces considerable oxidative stress and disrupts cellular signaling. This study examines the effect of ACR on IFNα mediated anti‐viral signaling in hepatic cells. Our data demonstrate that relevant concentrations of ACR significantly inhibit interferon‐alpha mediated JAK/Stat signaling, leading to reduced expression of anti‐viral proteins. ACR dramatically inhibits IFN‐induced tyrosine phosphorylation of both STAT1 and STAT2, and their upstream kinases, JAK1 and Tyk2. A corresponding decrease is observed in the nuclear translocation of phospho‐STAT1 and 2. Acrolein down regulated IFNα. inducible expression of anti‐HCV proteins such as PKR, OAS, ISG15 and ISG54, primarily by decreasing ISRE‐controlled gene transcription. This study identifies acrolein, a derivative of lipid peroxidation and a common environmental pollutant, as a potential cofactor that contributes to poor treatment outcomes and failure of IFNα therapy.