Analysis of the transcriptional networks underpinning the activation of murine macrophages by inflammatory mediators.
Analysis of the transcriptional networks underpinning the activation of murine macrophages by inflammatory mediators.
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DOI：
10.1189/jlb.6hi0313-169r
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发表时间：
2014-08
影响因子：
5.5
通讯作者：
Freeman TC
中科院分区：
文献类型：
--
作者：
Raza S;Barnett MW;Barnett-Itzhaki Z;Amit I;Hume DA;Freeman TC
转录组学数据的分析揭示了LPS反应可以细分为比以前考虑的更大数量的共调节基因子集。巨噬细胞对TLR 4激动剂LPS的反应是一个由信号通路和转录因子组成的复杂调控网络控制的连续转录级联反应。目前已知至少有两种不同的途径被TLR 4参与，并且通过它们对衔接子分子MyD 88的依赖性来区分。我们已经使用基因表达微阵列来确定三个变量中的每一个的影响-LPS剂量，LPS与IFN-β和IFN-γ，和遗传背景-对小鼠BMDM的转录反应。对从数据生成的相关网络的分析已经确定了巨噬细胞转录网络内的子网络或模块，这些子网络或模块被这些变量选择性地激活。我们已经确定了小鼠品系特异性特征，包括一个富含SLE易感性候选者的模块。在不同处理所特有的基因模块中，我们发现了由I型IFN诱导而不是由LPS处理诱导的基因模块，这表明LPS-TLR 4信号反馈控制中的另一层复杂性。我们还观察到，补体系统的激活与已知的MHC 2类基因的激活一样，依赖于IFN-γ信号传导。总之，这些数据进一步突出了控制巨噬细胞活化的调节系统的精致性质，它们与疾病抗性/易感性的可能相关性，以及这些细胞对促炎刺激的适当反应。
Analysis of transcriptomics data reveals the LPS response can be subdivided into a larger number of co-regulated gene subsets than previously considered. Macrophages respond to the TLR4 agonist LPS with a sequential transcriptional cascade controlled by a complex regulatory network of signaling pathways and transcription factors. At least two distinct pathways are currently known to be engaged by TLR4 and are distinguished by their dependence on the adaptor molecule MyD88. We have used gene expression microarrays to define the effects of each of three variables—LPS dose, LPS versus IFN-β and -γ, and genetic background—on the transcriptional response of mouse BMDMs. Analysis of correlation networks generated from the data has identified subnetworks or modules within the macrophage transcriptional network that are activated selectively by these variables. We have identified mouse strain-specific signatures, including a module enriched for SLE susceptibility candidates. In the modules of genes unique to different treatments, we found a module of genes induced by type-I IFN but not by LPS treatment, suggesting another layer of complexity in the LPS-TLR4 signaling feedback control. We also observe that the activation of the complement system, in common with the known activation of MHC class 2 genes, is reliant on IFN-γ signaling. Taken together, these data further highlight the exquisite nature of the regulatory systems that control macrophage activation, their likely relevance to disease resistance/susceptibility, and the appropriate response of these cells to proinflammatory stimuli.