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

Hepatology. 2006 Oct;44(4):896-906. doi: 10.1002/hep.21312.

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-alpha. 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-alpha 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-alpha 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.

MeSH terms

  • Animals
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • CHO Cells / drug effects
  • Cell Line / drug effects
  • Cricetinae
  • Cricetulus
  • Cytokines / pharmacology*
  • Cytokines / therapeutic use
  • Flavivirus / genetics
  • Gene Expression Regulation, Viral / drug effects*
  • Hepacivirus / genetics
  • Hepatitis B virus / genetics
  • Hepatitis, Viral, Human / drug therapy*
  • Hepatitis, Viral, Human / virology
  • Hepatocytes / metabolism
  • Hepatocytes / virology
  • Humans
  • Interferon-alpha / adverse effects
  • Interferon-alpha / pharmacology*
  • Interferon-alpha / therapeutic use
  • Interferons
  • Interleukins / pharmacology*
  • Interleukins / therapeutic use
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • RNA / analysis
  • RNA / metabolism
  • Receptors, Interleukin / metabolism
  • STAT1 Transcription Factor / metabolism
  • Viral Load
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Cytokines
  • IFNL1 protein, human
  • Interferon-alpha
  • Interleukins
  • Receptors, Interleukin
  • STAT1 Transcription Factor
  • RNA
  • Interferons