IL-10 limits the magnitude of inflammatory gene expression following microbial stimuli and is essential to prevent inflammatory disease; however, the molecular basis for IL-10–mediated inhibition remains elusive. Using a genome-wide approach, we demonstrate that inhibition of transcription is the primary mechanism for IL-10–mediated suppression in LPS-stimulated macrophages and that inhibited genes can be divided into two clusters. Genes in the first cluster are inhibited only if IL-10 is included early in the course of LPS stimulation and is strongly enriched for IFN-inducible genes. Genes in the second cluster can be rapidly suppressed by IL-10 even after transcription is initiated, and this is associated with suppression of LPS-induced enhancer activation. Interestingly, the ability of IL-10 to rapidly suppress active transcription exhibits a delay following LPS stimulation. Thus, a key pathway for IL-10–mediated suppression involves rapid inhibition of enhancer function during the secondary phase of the response to LPS.
This work was supported by National Institutes of Health Grant R01-AI100114 (to B.H.H.); D.C.d.O. was supported by Grant 2015/02610-6 from the Sao Paulo Research Foundation. C.M.M. is supported by National Institutes of Health Grant 5T32HD040128. S.B.S. is supported by National Institutes of Health Grant DK034854 and the Wolpow Family Chair in Inflammatory Bowel Disease Treatment and Research. S.B.S. and B.H.H. are supported by the Helmsley Charitable Trust.
The data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/genbank) under accession number GSE86170.
Abbreviations used in this article:
- bone marrow–derived macrophage
- chromatin immunoprecipitation followed by DNA sequencing
- false discovery rate
- monomethylation of histone H3 at lysine 4
- acetylation of histone H3 at lysine 27
- precursor mRNA
- RNA sequencing
- Received October 18, 2016.
- Accepted January 30, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.