The role of dual specificity phosphatase 1 in the anti-inflammatory effects of the glucocorticoid receptor

Glucocorticoids (GCs) have been used for decades in the treatment of chronic inflammatory and autoimmune diseases, thanks to their powerful anti‐inflammatory properties. However, long term treatment can lead to deleterious side effects, and some patients also experience resistance to their therapeutic effects. GCs act through the glucocorticoid receptor (GR) to regulate transcription both positively and negatively. Negative regulation of transcription involves a process known as transrepression, in which ligand‐activated GR impairs transcriptional activation by nuclear factor κB (NF‐κB) and other transcription factors. It is widely believed that transrepression accounts for most of the anti‐inflammatory effects of GCs, whereas the activation of transcription (transactivation) is responsible for most side effects of GCs. Based on this principle, several pharmaceutical companies are trying to identify selective GR modulators (SGRMs) that preferentially induce transrepression rather than transactivation. Such compounds are predicted to retain the anti‐inflammatory properties of classical GCs but cause fewer side effects. There are several problems with a dogma that equates anti‐inflammatory effects of GR with transcriptional repression. One is that GCs have long been known to destabilise many pro-inflammatory mRNAs, and this property is not explained by the transrepression model. Another issue is that GCs induce the expression of many factors with powerful anti-inflammatory effects. One of these is dual specificity phosphatase 1 (DUSP1), an enzyme that dephosphorylates and inactivates mitogen‐activated protein kinases. Studies of the Dusp1‐/‐ mouse have underlined the importance of the phosphatase in the antiinflammatory response to GCs. In this work, I investigated the role of DUSP1 in (1) the post‐transcriptional regulation of pro‐inflammatory mRNA stability by GCs and (2) the anti‐inflammatory actions of SGRMs. 1‐ The classical dexamethasone (dex) was shown to upregulate DUSP1 in mouse macrophages, and to inhibit the expression of cyclooxygenase 2 (COX‐2) in a manner that was partially dependent on DUSP1. Dex destabilised COX‐2 and interleukin 1α mRNAs, and this post‐transcriptional effect appeared to require DUSP1. 2‐ Two SGRMs were characterised and shown to preferentially mediate transrepression rather than transactivation. However, they were capable of inducing the expression of DUSP1 in several different cellular systems, and their capacity to inhibit the expression of COX‐2 was correlated with DUSP1 induction. Finally, several of the anti‐inflammatory effects of the SGRMs were found significantly impaired in mouse macrophages lacking DUSP1.EThOS - Electronic Theses Online ServiceGBUnited Kingdo