title: Inhibition of Inflammatory Gene Transcription by IL-10 Is Associated with Rapid Suppression of Lipopolysaccharide-Induced Enhancer Activation.
abstract: 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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Conaway
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Dalila C
authors.identifier: 0000-0001-5484-8072
authors.initials: DC
authors.lastname: de Oliveira
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.|Division of Emergency Medicine, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Christine M
authors.identifier: 0000-0002-8449-4954
authors.initials: CM
authors.lastname: McInnis
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, MA 02115; and.|Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; bhorwitz@partners.org.|Division of Emergency Medicine, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000235:genetics* / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D016753:Interleukin-10