TNF-α and IFN-α enhance influenza-A-virus-induced chemokine gene expression in human A549 lung epithelial cells

Lung epithelial cells are the primary cellular targets for respiratory virus pathogens such as influenza and parainfluenza viruses. Here, we have analyzed influenza A, influenza B and Sendai virus-induced chemokine response in human A549 lung epithelial cells. Influenza virus infection resulted in low CCL2/MCP-1, CCL5/RANTES, CXCL8/IL-8 and CXCL10/IP-10 production at late times of infection. However, when cells were pretreated with TNF-α or IFN-α, influenza-A-virus-induced chemokine production was greatly enhanced. Cytokine pretreatment resulted in enhanced expression of RIG-I, IKKε, interferon regulatory factor (IRF)1, IRF7 and p50 proteins. Most importantly, influenza-A-virus-induced DNA binding of IRF1, IRF3, IRF7 and NF-κB onto CXCL10 ISRE and NF-κB elements, respectively, was markedly enhanced in cytokine-pretreated cells. Our results suggest that IFN-α and TNF-α have a significant role in priming epithelial cells for higher cytokine and chemokine production in influenza A virus infection.