Chronic inflammation is an underlying issue seen in multiple debilitating diseases such as rheumatoid arthritis. Granulocyte macrophage-colony stimulating factor (GM-CSF) is a key cytokine that contributes to the development and sustainment of inflammation, in part, through the upregulation of C-C motif chemokine ligand 17 (CCL17). The binding of GM-CSF to its receptor activates JAK2 and STAT5 phosphorylation. This prompts the upregulation of JMJD3, IRF4 and subsequently CCL17 which is secreted out of the cell thus exacerbating the inflammatory microenvironment.
Glucocorticoids (GCs) are first line treatments used broadly in numerous inflammatory diseases. Dexamethasone (Dex) is a commonly prescribed GC, however long-term use and high dosage is associated adverse side effects. The relationship between dexamethasone and its ability to alleviate chronic inflammation is still not completely understood, highlighting the need to explore its inhibitory mechanisms and pathways.
We report here that in GM-CSF-mediated CCL17 inflammation, Dex has the ability to intervene with the STAT5 phosphorylation event in human monocytes and mouse macrophages. This interaction is seen to drastically suppress the expression of downstream regulatory proteins, including interferon regulatory factor 4 (IRF4), thus preventing the over secretion of CCL17. These findings provide evidence into how Dex mechanistically alleviates chronic inflammation. As a result, this knowledge can form the basis of new drug development that target more specific aspects of the signalling cascade, that either reduce or completely prevent the side effects that are commonly associated with long term glucocorticoid use.