title: Induction of proinflammatory cytokines in primary human macrophages by influenza A virus (H5N1) is selectively regulated by IFN regulatory factor 3 and p38 MAPK.
abstract: The hyperinduction of proinflammatory cytokines and chemokines such as TNF-alpha, IFN-beta, and CCL2/MCP-1 in primary human macrophages and respiratory epithelial cells by the highly pathogenic avian influenza H5N1 is believed to contribute to the unusual severity of human H5N1 disease. Here we show that TNF-alpha, IFN-beta, and IFN-lambda1 are the key mediators directly induced by the H5N1 virus in primary human macrophages. In comparison with human influenza (H1N1), the H5N1 virus more strongly activated IFN regulatory factor 3 (IRF3). IRF3 knockdown and p38 kinase inhibition separately and in combination led to a substantial reduction of IFN-beta, IFN-lambda1, and MCP-1 but only to a partial reduction of TNF-alpha. IRF3 translocation was independent of p38 kinase activity, indicating that IRF3 and p38 kinase are distinct pathways leading to cytokine production by H5N1 virus. We conclude that IRF3 and p38 kinase separately and predominantly contribute to H5N1-mediated induction of IFN-beta, IFN-lambda1, and MCP-1 but only partly control TNF-alpha induction. A more precise identification of the differences in the regulation of TNF-alpha and IFN-beta could provide novel targets for the design of therapeutic strategies for severe human H5N1 influenza and also for treating other causes of acute respiratory distress syndrome.
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Kenrie P Y
authors.initials: KP
authors.lastname: Hui
authors.forename: Suki M Y
authors.initials: SM
authors.lastname: Lee
authors.forename: Chung-yan
authors.initials: CY
authors.lastname: Cheung
authors.forename: Iris H Y
authors.initials: IH
authors.lastname: Ng
authors.forename: Leo L M
authors.initials: LL
authors.lastname: Poon
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.forename: Nancy Y Y
authors.initials: NY
authors.lastname: Ip
authors.forename: Allan S Y
authors.initials: AS
authors.lastname: Lau
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D004285:Dogs; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis; D007700:Kinetics; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D000095022:Interferon Lambda
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C111835:CCL2 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human