Epigenetic and transcriptional regulation of CCL17 production by glucocorticoids in arthritis
Tanya J. Lupancu,
Kevin M.C. Lee,
Mahtab Eivazitork,
Cecil Hor,
Andrew J. Fleetwood,
Andrew D. Cook,
Moshe Olshansky,
Stephen J. Turner,
Richard de Steiger,
Keith Lim,
John A. Hamilton,
Adrian A. Achuthan
Affiliations
Tanya J. Lupancu
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia
Kevin M.C. Lee
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia
Mahtab Eivazitork
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia
Cecil Hor
Department of Medicine, Western Health, The University of Melbourne, St Albans, VIC 3021, Australia
Andrew J. Fleetwood
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia; Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
Andrew D. Cook
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia
Moshe Olshansky
Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
Stephen J. Turner
Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
Richard de Steiger
Department of Surgery, Epworth HealthCare, The University of Melbourne, Richmond, VIC 3121, Australia
Keith Lim
Department of Medicine, Western Health, The University of Melbourne, St Albans, VIC 3021, Australia
John A. Hamilton
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia
Adrian A. Achuthan
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia; Corresponding author
Summary: Glucocorticoids (GCs) are potent anti-inflammatory agents and are broadly used in treating rheumatoid arthritis (RA) patients, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action. We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CCL17 has a non-redundant role in inflammatory arthritis. Here, we provide molecular evidence that GCs can suppress GM-CSF-mediated upregulation of IRF4 and CCL17 expression via downregulating JMJD3 expression and activity. In mouse models of inflammatory arthritis, GC treatment inhibited CCL17 expression and ameliorated arthritic pain-like behavior and disease. Significantly, GC treatment of RA patient peripheral blood mononuclear cells ex vivo resulted in decreased CCL17 production. This delineated pathway potentially provides new therapeutic options for the treatment of many inflammatory conditions, where GCs are used as an anti-inflammatory drug but without the associated adverse side effects.
