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.

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