Rheumatoid arthritis is a chronic inflammatory autoimmune disease, which leads to poor quality of life due to the debilitating effect of inflammation. Clinical trials in rheumatoid arthritis targetting the cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF) are showing promise although its mode of action remains largely unknown. We have recently shown that that GM-CSF drives CCL17 production via a new interferon regulatory factor 4 (IRF4)-dependent pathway in human monocytes and murine macrophages, as well as in vivo (Achuthan et al, JCI, 2016). Importantly, in arthritis and pain models IRF4-regulated CCL17 formation mediates the proinflammatory and algesic actions of GM-CSF.
Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents broadly used in anti-inflammatory therapy, albeit with adverse side effects assocated 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 on immune cells.
We report here that GM-CSF-induced CCL17 expression is inhibited by GCs in human monocytes and mouse macrophages. Moreover, we provide evidence for the first time that GCs suppress GM-CSF-induced IRF4 expression via regulating the expression and activity of JMJD3, which demethylases trimethylated-H3K27. Significantly, a recent study reported that synovial fluid from patients with rheumatoid arthritis had elevated levels of CCL17 as compared to healthy controls. We will provide molecular evidence for the anti-inflammatory actions of GCs in rheumatoid arthritis patient samples. The delineated pathway potentially provides new therapeutic options for the treatment of inflammatory diseases and their associated pain.