Synergistic Activation of Inflammatory Cytokine Genes by Interferon-γ-Induced Chromatin Remodeling and Toll-like Receptor Signaling
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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.
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The study sheds light on previously described immune-related transcriptional programs where assisted loading was not suggested but seems plausible in light of our findings.
“Our study also sheds light on previously described immune-related transcriptional programs where assisted loading was not suggested but seems plausible in light of our findings24, 56, 57.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [57]
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- Authors
- Qiao, Y., Giannopoulou, E. G., Chan, C. H., Park, S.-H., Gong, S., Chen, J., Hu, X., Elemento, O., & Ivashkiv, L. B.
- Affiliations
- Hospital for Special Surgery (US)
- Cornell University (US)
- Corresponding author
- Ivashkiv, Lionel B.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 39
- Issue
- 3
- Pages
- 454-469
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3857147
- OpenAlex
- W2070340931
- Cited by
- 330
- References
- 48
- Citations by year
- 2026: 29 · 2025: 26 · 2024: 28 · 2023: 38 · 2022: 30 · 2021: 19 · 2020: 11 · 2019: 21 · 2018: 26 · 2017: 25 · 2016: 26 · 2015: 30 · 2014: 19 · 2013: 1
- FWCI
- 14.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000457, 2r01ai046712-26)
- National Institute of Allergy and Infectious Diseases (R01-AI046712, R01AI044938)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056729, R01AR050401, R01AR046713)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interferon-gamma, Toll-like receptor signaling, TLR4, chromatin remodeling, macrophages, STAT1, IRF1, histone acetylation, enhancers, promoter, TNF-α, interleukin-6, IL12B, JAK inhibitors, transcriptional priming, innate immunity
- MeSH terms
- Acetylation, Cells, Cultured, Enzyme Activation, Histones, Humans, Interferon-gamma, Macrophages, Promoter Regions, Genetic, Protein Binding, RNA Polymerase II, Transcription, Genetic, Signal Transduction, Interleukin-6, Cytokines, Chromatin Assembly and Disassembly, Tumor Necrosis Factors, STAT1 Transcription Factor, Interferon Regulatory Factor-1, Toll-Like Receptors, Janus Kinases, Interleukin-12 Subunit p40
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