Abstract
Controversy currently exists about the ability of human neutrophils to produce IL-6. Here, we show that the chromatin organization of the IL-6 genomic locus in human neutrophils is constitutively kept in an inactive configuration. However, we also show that upon exposure to stimuli that trigger chromatin remodelling at the IL-6 locus, such as ligands for TLR8 or, less efficiently, TLR4, highly purified neutrophils express and secrete IL-6. In TLR8-activated neutrophils, but not monocytes, IL-6 expression is preceded by the induction of a latent enhancer located 14 kb upstream of the IL-6 transcriptional start site. In addition, IL-6 induction is potentiated by endogenous TNFα, which prolongs the synthesis of the IκBζ co-activator and sustains C/EBPβ recruitment and histone acetylation at IL-6 regulatory regions. Altogether, these data clarify controversial literature on the ability of human neutrophils to generate IL-6 and uncover chromatin-dependent layers of regulation of IL-6 in these cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Autocrine Communication / drug effects
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Autocrine Communication / genetics*
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Chromatin Assembly and Disassembly* / drug effects
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Enhancer Elements, Genetic / genetics
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Genetic Loci
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Granulocyte Colony-Stimulating Factor / genetics
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Granulocyte Colony-Stimulating Factor / metabolism
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Histones / metabolism
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Humans
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I-kappa B Proteins / metabolism
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Imidazoles / pharmacology
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Inflammation / pathology
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin 1 Receptor Antagonist Protein / metabolism
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Interleukin-12 Receptor beta 1 Subunit / genetics
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Interleukin-12 Receptor beta 1 Subunit / metabolism
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Interleukin-6 / biosynthesis
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Interleukin-6 / genetics*
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Ligands
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Mice, Inbred C57BL
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Models, Biological
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Neutrophil Activation / drug effects
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Neutrophil Activation / genetics*
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Neutrophils / drug effects
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Neutrophils / metabolism*
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Nuclear Proteins / metabolism
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Peritoneum / pathology
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Protein Processing, Post-Translational
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Toll-Like Receptors / metabolism
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Transcription Factors / metabolism
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Histones
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I-kappa B Proteins
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IL6 protein, human
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Imidazoles
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-12 Receptor beta 1 Subunit
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Interleukin-6
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Ligands
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NFKBIZ protein, human
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Nuclear Proteins
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RNA, Messenger
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TNF protein, human
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Toll-Like Receptors
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Granulocyte Colony-Stimulating Factor
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resiquimod