ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus.
We have previously demonstrated that macrophages stimulated in the presence of immune complexes produce high levels of IL-10. We now examine the mechanism of IL-10 superinduction. We report that the enhanced production of IL-10 correlates with a rapid and enhanced activation of two MAPKs, ERK and p38. The inhibition of either ERK or p38 prevented IL-10 induction, indicating that both MAPKs were required for IL-10 synthesis. By chromatin immunoprecipitation assay, we demonstrate that activation of ERK leads to the phosphorylation of serine 10 on histone H3 at the il-10 gene, making the promoter more accessible to transcription factors generated in response to p38 activation. Inhibition of ERK activation prevented histone modifications, and decreased the binding of Sp1 and STAT3 to the IL-10 promoter. We conclude that the activation of ERK following FcgammaR ligation leads to a remodeling of the chromatin at the il-10 locus, making it more accessible to transcription factors. The rapid and transient regulation of transcription factor accessibility to the IL-10 promoter by MAPK activation represents a novel way that the production of this cytokine is regulated.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Mark
M
Lucas
Xia
X
Zhang
Vikram
V
Prasanna
David M
DM
Mosser
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000235:genetics*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017452:Receptors, IgG / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D012694:Serine / Q000737:chemistry; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D000936:Antigen-Antibody Complex; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D017452:Receptors, IgG; D050796:STAT3 Transcription Factor; D016329:Sp1 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; D012694:Serine; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases