Interleukin‐29 uses a type 1 interferon‐like program to promote antiviral responses in human hepatocytes†

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Abstract
Interleukin‐28A (IL‐28A), IL‐28B and IL‐29 are a family of class II cytokines that stimulate antiviral responses through a heterodimeric receptor that is distinct from the type I interferon (IFN) receptor. To better understand how this newly described family of cytokines regulates the antiviral state, we compared various cellular responses elicited by IL‐29 and IFN‐α. Here we show that these cytokines stimulate similar patterns of signal transducer and activator of transcription 1 (STAT‐1), ‐2, ‐3, and ‐5 phosphorylation and nearly identical patterns of gene expression when analyzed in two distinct cell types by microarray analysis. Interestingly, the IL‐29 receptor is preferentially expressed on primary hepatocytes within normal liver and pegylated forms of IL‐29 and IFN‐α induced equivalent 2′5′ oligoadenylate synthetase (OAS) and MX1 gene expression in this cell type. Pegylated IL‐29 also produced a significant reduction in human hepatitis B and hepatitis C viral load in vitro and reduced the cytopathic effect caused by the fully replicating flavivirus, West Nile virus. In conclusion, IL‐29 and IFN‐α stimulate identical antiviral responses despite their utilization of different receptors. This fact, combined with significant receptor expression in hepatitis virus‐infected livers, suggests that IL‐29 may have therapeutic value against chronic viral hepatitis in human patients. (HEPATOLOGY 2006;44:896–906.)