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J Biol Chem. 2018 Jul 20;293(29):11415-11423. doi: 10.1074/jbc.RA118.002416. Epub 2018 Jun 5.

Epigenetic and transcriptional regulation of IL4-induced CCL17 production in human monocytes and murine macrophages.

Author information

1
From the Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050 and.
2
the Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, Victoria 3021, Australia.
3
From the Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050 and aaa@unimelb.edu.au.

Abstract

Interleukin 4 (IL4) is generally viewed as a Th2 cytokine capable of polarizing macrophages into an anti-inflammatory phenotype, whereas granulocyte macrophage-colony-stimulating factor (GM-CSF) is often viewed as a proinflammatory cytokine with part of this function due to its action on monocytes/macrophages. Paradoxically, these two cytokines act additively to enhance the in vitro differentiation of dendritic cells from precursors such as monocytes. One up-regulated marker of an IL4-polarized M2 macrophage is the chemokine (C-C motif) ligand 17 (CCL17), which we have recently reported to be induced by GM-CSF in monocytes/macrophages in an interferon regulatory factor 4 (IRF4)-dependent manner. In this study, we report that IL4 also induces CCL17 production by acting through IRF4 in human monocytes and murine macrophages. Furthermore, evidence is presented that IL4 up-regulates IRF4 expression at the epigenetic level by enhancing the expression and activity of jumonji domain-containing protein 3 (JMJD3) demethylase. Intriguingly, silencing the signal transducer and activator of transcription 6 (STAT6) gene led to a decrease in not only CCL17 formation, but also in that of its upstream regulators, JMJD3 and IRF4. Moreover, IL4 treatment of human monocytes resulted in an increased association of STAT6 to the promoter regions of the CCL17, IRF4, and JMJD3 genes. Thus, despite their vastly different functions, IL4 and GM-CSF appear to share elements of a common signaling pathway in regulating CCL17 production in human monocytes and murine macrophages.

KEYWORDS:

STAT transcription factor; chemokine; cytokine; dendritic cell; epigenetics; interferon regulatory factor (IRF); interleukin; macrophage; monocyte; signal transduction

PMID:
29871928
PMCID:
PMC6065189
DOI:
10.1074/jbc.RA118.002416
[Indexed for MEDLINE]
Free PMC Article

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