Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo
Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo
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DOI：
10.1189/jlb.1008671
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发表时间：
2009-05-01
影响因子：
5.5
通讯作者：
Klinman, Dennis M.
中科院分区：
文献类型：
--
作者：
Klaschik, Sven;Tross, Debra;Klinman, Dennis M.
表达未甲基化CpG基序的细菌DNA与TLR 9结合，从而刺激广泛的保护性先天免疫应答。虽然CpG介导的信号转导已被研究，TLR 9依赖的基因表达的范围是不完全理解。为了解决这些问题，用免疫刺激性CpG寡核苷酸（ODN）处理小鼠，并通过微阵列监测从30分钟到3天的脾mRNA水平。通过对这些实验数据进行生物信息学分析的独特应用，本研究首次描述了负责TLR 9介导的基因表达的复杂调控网络。目前的结果是第一次建立，CpG诱导的刺激先天免疫系统的收益在多个波随着时间的推移，基因上调是由少量的时间激活的“主要诱导剂”和“次要诱导剂”介导的。对TNF敲除小鼠的另一项研究支持以下结论：通过我们的生物信息学分析鉴定的调控网络准确地鉴定了体内CpG ODN驱动的基因-基因相互作用。同样重要的是，这项工作确定了嵌入在信号级联中的反调节机制，该机制抑制了由CpG DNA刺激在体内触发的促炎反应。识别这些网络相互作用提供了新的和全球性的见解调节TLR 9介导的基因激活，提高我们的理解TLR介导的宿主防御，并促进干预措施的发展，旨在优化随后的反应的性质和持续时间。J. Leukoc. 85：788-795; 2009.
Bacterial DNA expressing unmethylated CpG motifs binds to TLR9, thereby stimulating a broadly protective, innate immune response. Although CpG-mediated signal transduction has been studied, the scope of TLR9-dependent gene expression is incompletely understood. To resolve these issues, mice were treated with immunostimulatory CpG oligonucleotides (ODN) and splenic mRNA levels monitored from 30 min through 3 days by microarray. Through the unique application of bioinformatic analysis to these experimental data, this study is the first to describe the complex regulatory networks responsible for TLR9-mediated gene expression. Current results are the first to establish that CpG-induced stimulation of the innate immune system proceeds in multiple waves over time, and gene up-regulation is mediated by a small number of temporally activated "major inducers" and "minor inducers". An additional study of TNF knockout mice supports the conclusion that the regulatory networks identified by our bioinformatic analysis accurately identified CpG ODN-driven gene-gene interactions in vivo. Equally important, this work identifies the counter-regulatory mechanisms embedded within the signaling cascade that suppresses the proinflammatory response triggered in vivo by CpG DNA stimulation. Identifying these network interactions provides novel and global insights into the regulation of TLR9-mediated gene activation, improves our understanding of TLR-mediated host defense, and facilitates the development of interventions designed to optimize the nature and duration of the ensuing response. J. Leukoc. Biol. 85: 788-795; 2009.