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

doi:10.1016/j.isci.2023.108079

Epigenetic and transcriptional regulation of CCL17 production by glucocorticoids in arthritis

iScience. 2023 Sep 27;26(10):108079. doi: 10.1016/j.isci.2023.108079. eCollection 2023 Oct 20.

Authors

Affiliations

¹ Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia.
² Department of Medicine, Western Health, The University of Melbourne, St Albans, VIC 3021, Australia.
³ Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
⁴ Department of Microbiology, Monash University, Clayton, VIC 3800, Australia.
⁵ Department of Surgery, Epworth HealthCare, The University of Melbourne, Richmond, VIC 3121, Australia.

Abstract

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.

Keywords: Epigenetics; Molecular mechanism of gene regulation; Orthopedics.