Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils

Maili Zimmermann; Francisco Bianchetto Aguilera; Monica Castellucci; Marzia Rossato; Sara Costa; Claudio Lunardi; Renato Ostuni; Giampiero Girolomoni; Gioacchino Natoli; Flavia Bazzoni; Nicola Tamassia; Marco A Cassatella

doi:10.1038/ncomms7061

Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils

Nat Commun. 2015 Jan 23:6:6061. doi: 10.1038/ncomms7061.

Affiliations

¹ Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, 37134 Verona, Italy.
² Department of Medicine, Section of Internal Medicine, University of Verona, 37134 Verona, Italy.
³ Department of Experimental Oncology, European Institute of Oncology (IEO), I-20139 Milan, Italy.
⁴ Department of Medicine, Section of Dermatology and Venereology, University of Verona, 37126 Verona, Italy.

PMID: 25616107
DOI: 10.1038/ncomms7061

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

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
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*

Substances

Adaptor Proteins, Signal Transducing
Histones
I-kappa B Proteins
IL6 protein, human
Imidazoles
Interleukin 1 Receptor Antagonist Protein
Interleukin-12 Receptor beta 1 Subunit
Interleukin-6
Ligands
NFKBIZ protein, human
Nuclear Proteins
RNA, Messenger
TNF protein, human
Toll-Like Receptors
Transcription Factors
Tumor Necrosis Factor-alpha
Granulocyte Colony-Stimulating Factor
resiquimod