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

Research output: Contribution to journalArticle

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 IκBΧ 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.

Original languageEnglish
Article number6061
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)
  • Medicine(all)

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  • Cite this

    Zimmermann, M., Aguilera, F. B., Castellucci, M., Rossato, M., Costa, S., Lunardi, C., Ostuni, R., Girolomoni, G., Natoli, G., Bazzoni, F., Tamassia, N., & Cassatella, M. A. (2015). Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils. Nature Communications, 6, [6061]. https://doi.org/10.1038/ncomms7061