Title | Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Qiao Y, Giannopoulou EG, Chan CHin, Park S-H, Gong S, Chen J, Hu X, Elemento O, Ivashkiv LB |
Journal | Immunity |
Volume | 39 |
Issue | 3 |
Pagination | 454-69 |
Date Published | 2013 Sep 19 |
ISSN | 1097-4180 |
Keywords | Acetylation, Cells, Cultured, Chromatin Assembly and Disassembly, Cytokines, Enzyme Activation, Histones, Humans, Interferon Regulatory Factor-1, Interferon-gamma, Interleukin-12 Subunit p40, Interleukin-6, Janus Kinases, Macrophages, Promoter Regions, Genetic, Protein Binding, RNA Polymerase II, Signal Transduction, STAT1 Transcription Factor, Toll-Like Receptors, Transcription, Genetic, Tumor Necrosis Factors |
Abstract | Synergistic activation of inflammatory cytokine genes by interferon-γ (IFN-γ) and Toll-like receptor (TLR) signaling is important for innate immunity and inflammatory disease pathogenesis. Enhancement of TLR signaling, a previously proposed mechanism, is insufficient to explain strong synergistic activation of cytokine production in human macrophages. Rather, we found that IFN-γ induced sustained occupancy of transcription factors STAT1, IRF-1, and associated histone acetylation at promoters and enhancers at the TNF, IL6, and IL12B loci. This priming of chromatin did not activate transcription but greatly increased and prolonged recruitment of TLR4-induced transcription factors and RNA polymerase II to gene promoters and enhancers. Priming sensitized cytokine transcription to suppression by Jak inhibitors. Genome-wide analysis revealed pervasive priming of regulatory elements by IFN-γ and linked coordinate priming of promoters and enhancers with synergistic induction of transcription. Our results provide a synergy mechanism whereby IFN-γ creates a primed chromatin environment to augment TLR-induced gene transcription. |
DOI | 10.1016/j.immuni.2013.08.009 |
Alternate Journal | Immunity |
PubMed ID | 24012417 |
PubMed Central ID | PMC3857147 |
Grant List | R01 AR046713 / AR / NIAMS NIH HHS / United States R01 AI046712 / AI / NIAID NIH HHS / United States R01 AR056729 / AR / NIAMS NIH HHS / United States R01 AR050401 / AR / NIAMS NIH HHS / United States UL1 TR000457 / TR / NCATS NIH HHS / United States R01 AI044938 / AI / NIAID NIH HHS / United States |