Granulocyte macrophage colony-stimulating factor induces CCL17 pro uction via IRF4 to mediate inflammation

被引：127

作者：

Achuthan, Adrian ^{[1
]}

Cook, Andrew D. ^{[1
]}

Lee, Ming-Chin ^{[1
]}

Saleh, Reem ^{[1
]}

Khiew, Hsu-Wei ^{[1
]}

Chang, Melody W. N. ^{[1
]}

Louis, Cynthia ^{[1
]}

Fleetwood, Andrew J. ^{[1
]}

Lacey, Derek C. ^{[1
,2
,3
]}

Christensen, Anne D. ^{[1
]}

Frye, Ashlee T. ^{[1
]}

Lam, Pui Yeng ^{[1
]}

Kusano, Hitoshi ^{[1
]}

Nomura, Koji ^{[1
,4
]}

Steiner, Nancy ^{[5
]}

Foerster, Irmgard ^{[5
]}

Nutt, Stephen L. ^{[2
]}

Olshansky, Moshe ^{[6
]}

Turner, Stephen J. ^{[6
]}

Hamilton, John A. ^{[1
]}

机构：

[1] Univ Melbourne, Royal Melbourne Hosp, Dept Med, Parkville, Vic 3050, Australia

[2] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia

[3] Univ Melbourne, Dept Med Biol, Parkville, Vic 3050, Australia

[4] Osaka Univ, Dept Orthoped Surg, Osaka, Japan

[5] Univ Bonn, Life & Med Sci Inst, Immunol & Environm, Bonn, Germany

[6] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3050, Australia

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2016年 / 126卷 / 09期

基金：

英国医学研究理事会; 澳大利亚研究理事会;

关键词：

DENDRITIC CELLS; GM-CSF; EXPERIMENTAL OSTEOARTHRITIS; UNWANTED VARIATION; GENE-EXPRESSION; CC-CHEMOKINE; KEY MEDIATOR; ARTHRITIS; ACTIVATION; RESPONSES;

D O I：

10.1172/JCI87828

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokine-independent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.

引用

页码：3453 / 3466

页数：14

共 65 条

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IRF4 in Dendritic Cells Inhibits IL-12 Production and Controls Th1 Immune Responses against Leishmania major [J].