title: Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation.
abstract: 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.
authors.forename: Adrian
authors.initials: A
authors.lastname: Achuthan
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cook
authors.forename: Ming-Chin
authors.initials: MC
authors.lastname: Lee
authors.forename: Reem
authors.initials: R
authors.lastname: Saleh
authors.forename: Hsu-Wei
authors.initials: HW
authors.lastname: Khiew
authors.forename: Melody W N
authors.initials: MW
authors.lastname: Chang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Louis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fleetwood
authors.forename: Derek C
authors.initials: DC
authors.lastname: Lacey
authors.forename: Anne D
authors.initials: AD
authors.lastname: Christensen
authors.forename: Ashlee T
authors.initials: AT
authors.lastname: Frye
authors.forename: Pui Yeng
authors.initials: PY
authors.lastname: Lam
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kusano
authors.forename: Koji
authors.initials: K
authors.lastname: Nomura
authors.forename: Nancy
authors.initials: N
authors.lastname: Steiner
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.forename: Moshe
authors.initials: M
authors.lastname: Olshansky
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D001168:Arthritis / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D054414:Chemokine CCL17 / Q000378:metabolism*; D020868:Gene Silencing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006579:Heterozygote; D006801:Humans; D007249:Inflammation; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010146:Pain; D059408:Pain Management; D010538:Peritonitis / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D054414:Chemokine CCL17; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D056484:Jumonji Domain-Containing Histone Demethylases; D000099218:Interferon Regulatory Factor-4; C106230:CCL17 protein, human; C499538:Ccl17 protein, mouse; C524220:KDM6B protein, human