Reference - Detail
|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.|
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.
|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*|
|DNA material||pGL4-phIL6 (RDB07313)|