RRC ID 32716
Author Zimmermann M, Aguilera FB, Castellucci M, Rossato M, Costa S, Lunardi C, Ostuni R, Girolomoni G, Natoli G, Bazzoni F, Tamassia N, Cassatella MA.
Title Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils.
Journal Nat Commun
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.
Volume 6
Pages 6061
Published 2015-1-23
DOI 10.1038/ncomms7061
PII ncomms7061
PMID 25616107
MeSH Animals Autocrine Communication / drug effects Autocrine Communication / genetics* Chromatin Assembly and Disassembly* / drug effects Enhancer Elements, Genetic / genetics Genetic Loci Granulocyte Colony-Stimulating Factor / genetics Granulocyte Colony-Stimulating Factor / metabolism Histones / metabolism Humans I-kappa B Proteins / metabolism Imidazoles / pharmacology Inflammation / pathology Interleukin 1 Receptor Antagonist Protein / genetics Interleukin 1 Receptor Antagonist Protein / metabolism Interleukin-12 Receptor beta 1 Subunit / genetics Interleukin-12 Receptor beta 1 Subunit / metabolism Interleukin-6 / biosynthesis Interleukin-6 / genetics* Ligands Mice, Inbred C57BL Models, Biological Neutrophil Activation / drug effects Neutrophil Activation / genetics* Neutrophils / drug effects Neutrophils / metabolism* Nuclear Proteins / metabolism Peritoneum / pathology Promoter Regions, Genetic / genetics Protein Binding / drug effects Protein Processing, Post-Translational RNA, Messenger / genetics RNA, Messenger / metabolism Toll-Like Receptors / metabolism Transcription Factors / metabolism Tumor Necrosis Factor-alpha / metabolism*
IF 12.121
Times Cited 44
DNA material pGL4-phIL6 (RDB07313)