Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation
Adrian Achuthan, Andrew D. Cook, Ming-Chin Lee, Reem Saleh, Hsu-Wei Khiew, Melody W.N. Chang, Cynthia Louis, Andrew J. Fleetwood, Derek C. Lacey, Anne D. Christensen, Ashlee T. Frye, Pui Yeng Lam, Hitoshi Kusano, Koji Nomura, Nancy Steiner, Irmgard Förster, Stephen L. Nutt, Moshe Olshansky, Stephen J. Turner, John A. Hamilton
Adrian Achuthan, Andrew D. Cook, Ming-Chin Lee, Reem Saleh, Hsu-Wei Khiew, Melody W.N. Chang, Cynthia Louis, Andrew J. Fleetwood, Derek C. Lacey, Anne D. Christensen, Ashlee T. Frye, Pui Yeng Lam, Hitoshi Kusano, Koji Nomura, Nancy Steiner, Irmgard Förster, Stephen L. Nutt, Moshe Olshansky, Stephen J. Turner, John A. Hamilton
View: Text | PDF
Research Article Inflammation

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

Adrian Achuthan, Andrew D. Cook, Ming-Chin Lee, Reem Saleh, Hsu-Wei Khiew, Melody W.N. Chang, Cynthia Louis, Andrew J. Fleetwood, Derek C. Lacey, Anne D. Christensen, Ashlee T. Frye, Pui Yeng Lam, Hitoshi Kusano, Koji Nomura, Nancy Steiner, Irmgard Förster, Stephen L. Nutt, Moshe Olshansky, Stephen J. Turner, John A. Hamilton

×

Figure 1

GM-CSF upregulates CCL17 expression in human monocytes and in vitro–derived and ex vivo murine macrophages.

Options: View larger image (or click on image) Download as PowerPoint
GM-CSF upregulates CCL17 expression in human monocytes and in vitro–deri...
(A–C) Human monocytes were treated with either PBS or GM-CSF (10 ng/ml) for 16 hours. (A) Heat map of significantly (P < 0.05) regulated cytokines (n = 3). (B) mRNA expression (qPCR) and (C) secreted CCL17 protein (ELISA) (n = 5). (D and E) Murine bone marrow cells were cultured in M-CSF (CSF-1) (5,000 U/ml) for 7 days to derive BMM before treating with either PBS or GM-CSF (20 ng/ml) for 16 hours in the absence of M-CSF. (D) mRNA expression and (E) secreted CCL17 protein (n = 4). (F) mRNA expression in thioglycolate-elicited peritoneal macrophages following treatment with PBS or GM-CSF (20 ng/ml) for 24 hours (n = 4). Graphs are plotted as mean ± SEM. ND, not detected. P values were obtained using a t test.