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

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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.

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

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This work was supported by grants from the National Health and Medical Research Council of Australia (to J. A. H. and A. D. C), and a Research Grant Support Scheme from the University of Melbourne (to A. A.). The authors declare that they have no conflicts of interest with the contents of this article.

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The abbreviations used are:

    IL4

    interleukin 4

    IRF4

    interferon regulatory factor 4

    GM-CSF

    granulocyte macrophage-colony-stimulating factor

    BMM

    bone marrow–derived macrophages

    TSS

    transcription start site

    STAT6

    signal transducer and activator of transcription 6

    JMJD3

    jumonji domain–containing protein 3

    KDM6B

    lysine-specific demethylase 6B

    qPCR

    quantitative PCR

    HPRT

    hypoxanthine-guanine phosphoribosyltransferase

    Ab

    antibody

    ANOVA

    analysis of variance.