Genome-wide analysis of STAT3 binding in vivo predicts effectors of the anti-inflammatory response in macrophages.
Inflammation is a powerful response of the immune system against invading pathogens, and must be cancelled when unneeded or otherwise death inevitably follows. In macrophages, the anti-inflammatory response (AIR) is driven by STAT3 upon IL-10 signaling. The role of STAT3 is to stimulate the expression of specific genes that in-turn suppress the transcription of proinflammatory genes. Here we describe a systematic approach to identify the elusive STAT3-controlled effectors of the AIR. In vivo STAT3-binding sites were identified by ChIP-seq, coupled to expression analysis by RNA-seq, both in resting and IL-10-treated peritoneal macrophages. We report the genomic targets of STAT3 and show that STAT3's transcriptional program during the AIR is highly specific to IL-10-stimulated macrophages, that STAT3 is a positive transcriptional regulator, and we predict severalputative AIR factors that merit further investigation. This is the first in-depth study of the AIR by next-generation sequencing and provides an unprecedented degree of detail into this fundamental physiologic response.
World Premier International (WPI) Immunology Frontier Research Centre (IFReC), Osaka University, Osaka, Japan.
Andrew Paul
AP
Hutchins
Stéphane
S
Poulain
Diego
D
Miranda-Saavedra
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics
D000893:Anti-Inflammatory Agents; D054316:Biomarkers, Pharmacological; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10