Impact of IL-27 on hepatocyte antiviral gene expression and function
Ramamurthy N., Boninsegna S., Adams R., Sahgal N., Lockstone H., Baban D., Marchi E., Klenerman P.
<ns4:p><ns4:bold>Background:</ns4:bold> Interleukin (IL)-27 is a member of the IL-6/IL-12 family of cytokines. It is a potent cytokine, with potential antiviral impact, and has been shown to play a role in modulating functions of diverse cell types, including Th1, Th2, and NK and B cells, demonstrating both pro- and anti-inflammatory roles. In hepatocytes, it is capable of inducing signal transducer and activator of transcription (STAT)1, STAT3 and interferon-stimulated genes.</ns4:p><ns4:p> <ns4:bold>Methods: </ns4:bold>To address its role in viral hepatitis, the antiviral activity of IL-27 against hepatitis C virus (HCV) and hepatitis B virus (HBV) was tested <ns4:italic>in vitro</ns4:italic> using cell-culture-derived infectious HCV (HCVcc) cell culture system and the HepaRG HBV cell culture model. To further investigate the impact of IL-27 on hepatocytes, Huh7.5 cells were treated with IL-27 to analyse the differentially expressed genes by microarray analysis. Furthermore, by quantitative PCR, we analyzed the up-regulation of chemokine <ns4:italic>(CXCL)-10</ns4:italic> in response to IL-27.</ns4:p><ns4:p> <ns4:bold>Results:</ns4:bold> In both HCV and HBV infection models, we observed only a modest direct antiviral effect. Microarray analysis showed that the up-regulated genes mostly belonged to antigen presentation and DNA replication pathways, and involved strong up-regulation of <ns4:italic>CXCL-10</ns4:italic>, a gene associated with liver inflammation. Overall, gene set enrichment analysis showed a striking correlation of these genes with those up-regulated in response to related cytokines in diverse cell populations.</ns4:p><ns4:p> <ns4:bold>Conclusion:</ns4:bold><ns4:italic> </ns4:italic>Our data indicate that IL-27 can have a significant pro-inflammatory impact <ns4:italic>in vitro</ns4:italic>, although the direct antiviral effect is modest. It may have a potential impact on hepatocyte function, especially chemokine expression and antigen presentation.</ns4:p>