Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK
Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK
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DOI：
10.4049/jimmunol.182.2.1088
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发表时间：
2009-01-15
影响因子：
4.4
通讯作者：
Peiris, J. S. Malik
中科院分区：
文献类型：
--
作者：
Hui, Kenrie P. Y.;Lee, Suki M. Y.;Peiris, J. S. Malik
高致病性禽流感H5 N1在原代人巨噬细胞和呼吸道上皮细胞中过度诱导促炎细胞因子和趋化因子，如TNF-α、IFN-β和CCL 2/MCP-1，被认为是导致人类H5 N1疾病异常严重的原因。在这里，我们表明，TNF-α，IFN-β和IFN-λ 1的主要介质直接诱导的H5 N1病毒在原代人巨噬细胞。与人流感（H1N1）相比，H5 N1病毒更强烈地激活IFN调节因子3（IRF 3）。IRF 3敲除和p38激酶抑制分别和联合导致IFN-β、IFN-λ 1和MCP-1的显著降低，但仅导致TNF-α的部分降低。IRF 3易位与p38激酶活性无关，表明IRF 3和p38激酶是导致H5 N1病毒产生细胞因子的不同途径。我们的结论是IRF 3和p38激酶分别和主要有助于H5 N1介导的IFN-β，IFN-λ 1和MCP-1的诱导，但只有部分控制TNF-α的诱导。更精确地鉴定TNF-α和IFN-β调节的差异可以为设计严重人类H5 N1流感的治疗策略以及治疗急性呼吸窘迫综合征的其他原因提供新的靶点。免疫学杂志，2009，182：1088-1098.
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-lambda 1 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-lambda 1, 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-lambda 1, 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. The Journal of Immunology, 2009, 182: 1088-1098.