Retinoic acid inducible gene-I and mda-5 are involved in influenza A virus-induced expression of antiviral cytokines

Activation of host cell antiviral responses is mediated by pattern recognition receptors. Cytoplasmic RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (mda-5) have been identified to function as receptors for double-stranded RNA. Here we show that interferon (IFN)-α pretreatment enhances influenza A virus-induced expression of IFN-α, IFN-β, interleukin (IL)-28 and IL-29 genes in human dendritic cells and epithelial cell lines. Both IFN-α and IFN-β strongly enhanced RIG-I and mda-5 mRNA and protein expression in these cell types. Expression of RIG-I and mda-5 gene constructs, but not that of TLR3, lead to a dramatic enhancement of IFN-β promoter driven transcription in influenza A virus-infected epithelial cells. Furthermore, dominant negative RIG-I gene construct inhibited influenza A virus-induced IFN-β promoter activity. In conclusion, our results show that in epithelial cells influenza A virus-induced antiviral cytokine gene expression is triggered by RIG-I and mda-5, whose expression is positively regulated by IFN-α.