IRF5 is required for late-phase TNF secretion by human dendritic cells
IRF5 is required for late-phase TNF secretion by human dendritic cells
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DOI：
10.1182/blood-2010-01-263020
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发表时间：
2010-06-03
期刊：
影响因子：
20.3
通讯作者：
Udalova, Irina A.
中科院分区：
文献类型：
--
作者：
Krausgruber, Thomas;Saliba, David;Udalova, Irina A.
炎症介质的空间和时间控制表达对于适当的免疫反应至关重要。在这项研究中，我们定义了干扰素调节因子 5 (IRF5) 在人树突状细胞 (DC) 分泌肿瘤坏死因子 (TNF) 中的作用。我们证明DC而非巨噬细胞具有高水平的IRF5蛋白，并且IRF5负责TNF的晚期表达，而巨噬细胞中不存在TNF。持续的 TNF 分泌对于 DC 强力激活 T 细胞至关重要。 TNF 基因位点的系统生物信息学和生化分析绘制了 IRF5 募集的 2 个位点：TNF 基因的 5' 上游和 3' 下游。值得注意的是，虽然 IRF5 可以直接与上游区域的 DNA 结合，但它向下游区域的募集取决于与 NF-kappa B RelA 的蛋白质-蛋白质相互作用。这项研究为 IRF5 用于调节基因表达的多种分子机制提供了新的见解，并暗示 RelA-IRF5 相互作用作为细胞特异性 TNF 表达调节的假定靶点。 （血。2010；115（22）：4421-4430）
Spatially and temporally controlled expression of inflammatory mediators is critical for an appropriate immune response. In this study, we define the role for interferon regulatory factor 5 (IRF5) in secretion of tumor necrosis factor (TNF) by human dendritic cells (DCs). We demonstrate that DCs but not macrophages have high levels of IRF5 protein, and that IRF5 is responsible for the late-phase expression of TNF, which is absent in macrophages. Sustained TNF secretion is essential for robust T-cell activation by DCs. Systematic bioinformatic and biochemical analyses of the TNF gene locus map 2 sites of IRF5 recruitment: 5' upstream and 3' downstream of the TNF gene. Remarkably, while IRF5 can directly bind to DNA in the upstream region, its recruitment to the downstream region depends on the protein-protein interactions with NF-kappa B RelA. This study provides new insights into diverse molecular mechanisms employed by IRF5 to regulate gene expression and implicates RelA-IRF5 interactions as a putative target for cell-specific modulation of TNF expression. (Blood. 2010; 115(22): 4421-4430)