Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation
- Achuthan, A; Cook, AD; Lee, MC; Saleh, R; Khiew, HW; Chang, MW; Louis, C; Fleetwood, AJ; Lacey, DC; Christensen, AD; Frye, AT; Lam, PY; Kusano, H; Nomura, K; Steiner, N; Forster, I; Nutt, SL; Olshansky, M; Turner, SJ; Hamilton, JA;
Publication Year 2016-09-01, Volume 126, Issue #9, Page 3453-66
- Journal Title
- J Clin Invest
- Publication Type
- Journal Article
- 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.
- WEHI Research Division(s)
- Molecular Immunology; Molecular Genetics Of Cancer
- PubMed ID
- Publisher's Version
- Open Access at Publisher's Site
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-10-04 09:29:21Last Modified: 2016-10-04 09:46:47