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 () and Marco A. Cassatella ()
Additional contact information
Maili Zimmermann: University of Verona
Francisco Bianchetto Aguilera: University of Verona
Monica Castellucci: University of Verona
Marzia Rossato: University of Verona
Sara Costa: University of Verona
Claudio Lunardi: Section of Internal Medicine, University of Verona
Renato Ostuni: European Institute of Oncology (IEO)
Giampiero Girolomoni: Section of Dermatology and Venereology, University of Verona
Gioacchino Natoli: European Institute of Oncology (IEO)
Flavia Bazzoni: University of Verona
Nicola Tamassia: University of Verona
Marco A. Cassatella: University of Verona

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7061

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