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

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

Author information

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.

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.

PMID:
25616107
DOI:
10.1038/ncomms7061
[Indexed for MEDLINE]

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