title: Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils.
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.
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Maili
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Francisco Bianchetto
authors.initials: FB
authors.lastname: Aguilera
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Castellucci
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Rossato
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Costa
authors.affiliation: Department of Medicine, Section of Internal Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), I-20139 Milan, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Ostuni
authors.affiliation: Department of Medicine, Section of Dermatology and Venereology, University of Verona, 37126 Verona, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Girolomoni
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), I-20139 Milan, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Bazzoni
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004742:Enhancer Elements, Genetic / Q000235:genetics; D056426:Genetic Loci; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008024:Ligands; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018375:Neutrophil Activation / Q000187:drug effects / Q000235:genetics*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010537:Peritoneum / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006657:Histones; D020672:I-kappa B Proteins; C508600:IL6 protein, human; D007093:Imidazoles; D053590:Interleukin 1 Receptor Antagonist Protein; D053711:Interleukin-12 Receptor beta 1 Subunit; D015850:Interleukin-6; D008024:Ligands; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; C439524:TNF protein, human; D051193:Toll-Like Receptors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; C402365:resiquimod