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.