Type I Interferons and the Cytokine TNF Cooperatively Reprogram the Macrophage Epigenome to Promote Inflammatory Activation

Overview

Journal Nat Immunol

Date 2017 Aug 22

PMID 28825701

Citations 125

Authors

Sung Ho Park

Kyuho Kang

Eugenia Giannopoulou

Yu Qiao

Keunsoo Kang

Geonho Kim

Kyung-Hyun Park-Min

Lionel B Ivashkiv

Affiliations

Soon will be listed here.

Abstract

Cross-regulation of Toll-like receptor (TLR) responses by cytokines is essential for effective host defense, avoidance of toxicity and homeostasis, but the underlying mechanisms are not well understood. Our comprehensive epigenomics approach to the analysis of human macrophages showed that the proinflammatory cytokines TNF and type I interferons induced transcriptional cascades that altered chromatin states to broadly reprogram responses induced by TLR4. TNF tolerized genes encoding inflammatory molecules to prevent toxicity while preserving the induction of genes encoding antiviral and metabolic molecules. Type I interferons potentiated the inflammatory function of TNF by priming chromatin to prevent the silencing of target genes of the transcription factor NF-κB that encode inflammatory molecules. The priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between interferons and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify previously unknown functions and mechanisms of action of these cytokines.

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