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Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4

机译：系统生物学方法确定ATF3为Toll样受体4的负调节剂

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The innate immune system is absolutely required for host defence, but, uncontrolled, it leads to inflammatory disease. This control is mediated, in part, by cytokines that are secreted by macrophages. Immune regulation is extraordinarily complex, and can be best investigated with systems approaches ( that is, using computational tools to predict regulatory networks arising from global, high-throughput data sets). Here we use cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor (TLR)-activated macrophages to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors. Network analysis predicted that ATF3 is part of a transcriptional complex that also contains members of the nuclear factor (NF)-kappa B family of transcription factors. Promoter analysis of the putative ATF3-regulated gene cluster demonstrated an over-representation of closely apposed ATF3 and NF-kappa B binding sites, which was verified by chromatin immunoprecipitation and hybridization to a DNA microarray. This cluster included important cytokines such as interleukin (IL)-6 and IL-12b. ATF3 and Rel ( a component of NF-kappa B) were shown to bind to the regulatory regions of these genes upon macrophage activation. A kinetic model of Il6 and Il12b messenger RNA expression as a function of ATF3 and NF-kappa B promoter binding predicted that ATF3 is a negative regulator of Il6 and Il12b transcription, and this hypothesis was validated using Atf3-null mice. ATF3 seems to inhibit Il6 and Il12b transcription by altering chromatin structure, thereby restricting access to transcription factors. Because ATF3 is itself induced by lipopolysaccharide, it seems to regulate TLR-stimulated inflammatory responses as part of a negative-feedback loop.
机译：先天免疫系统绝对是宿主防御所必需的，但不受控制会导致发炎性疾病。这种控制部分地由巨噬细胞分泌的细胞因子介导。免疫调节异常复杂，可以通过系统方法（即，使用计算工具预测由全球高通量数据集产生的调节网络）进行最佳调查。在这里，我们使用从Toll样受体（TLR）激活的巨噬细胞中获得的一组完整的转录组数据进行聚类分析，以鉴定一组明显受激活的转录因子3（ATF3）调控的基因。 / ATF家族的转录因子。网络分析预测ATF3是转录复合体的一部分，该复合体还包含核因子（NF）-κB转录因子家族成员。对假定的ATF3调控的基因簇的启动子分析表明，紧密结合的ATF3和NF-κB结合位点的过量表达，已通过染色质免疫沉淀和与DNA微阵列的杂交得到证实。该簇包括重要的细胞因子，例如白介素（IL）-6和IL-12b。巨噬细胞激活后，ATF3和Rel（NF-κB的一种成分）与这些基因的调节区结合。根据ATF3和NF-κB启动子结合的函数，Il6和Il12b信使RNA表达的动力学模型预测ATF3是Il6和Il12b转录的负调节剂，并且使用Att3无效小鼠验证了这一假设。 ATF3似乎通过改变染色质结构来抑制Il6和Il12b的转录，从而限制了对转录因子的访问。由于ATF3本身是由脂多糖诱导的，因此它作为负反馈环的一部分似乎可以调节TLR刺激的炎症反应。

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