Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo

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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.