The role of interferon regulatory factor 3 and p38 in influenza a virus induced pro-inflammatory cytokines

Abstract

The hyperinduction of pro-inflammatory cytokines and chemokines such as TNF-α, IFN-β, and CCL2/MCP-1 in primary human macrophages by the highly pathogenic avian influenza H5N1 is believed to contribute to the unusual severity of human H5N1 disease. Here we show that TNF-α and IFN-β are the key mediators directly induced by the H5N1 virus in primary human macrophages. In comparison to human influenza (H1N1), the H5N1 virus more strongly activated interferon regulatory factor 3 (IRF3). IRF3 knock-down and p38 kinase inhibition separately and in combination led to a dramatic reduction of IFN-β and MCP-1 but only to a partial reduction of TNF-α. IRF3 translocation was independent of p38 activity indicating that IRF3 and p38 are distinct pathways leading to cytokine production by H5N1 virus. We conclude that IRF3 and p38 kinase separately and predominantly contribute to H5N1-mediated hyper-induction of IFN-β and MCP-1 but only partly control TNF-α induction. A more precise identification of the differences in the regulation of TNF-α and IFN-β may provide novel strategies for the design of therapeutic strategies for severe human H5N1 influenza and also for treating other causes of acute respiratory disease syndrome.