Endocrine Abstracts

Glucocorticoids (GCs) are steroid hormones, products of the hypothalamic–pituitary–adrenal axis. Synthetic GCs, such as dexamethasone, have been widely used in the treatment of inflammatory diseases like rheumatoid arthritis or asthma, but their long-term use causes severe side effects (osteoporosis, diabetes, hypertension, etc). The ligand-bound GC receptor (GR) can activate gene expression via binding to GC response elements (GREs), a mechanism known as transactivation; or it can inhibit gene expression via interactions with other transcription factors such as NF-κB (known as transrepression). It is commonly thought that transrepression is responsible for the therapeutic effects of the GCs, whereas transactivation accounts for most side effects. Ligands that preferentially induce the transrepression rather than the transactivation function of GR are expected to retain anti-inflammatory properties whilst causing fewer side effects. Such compounds are known as selective glucocorticoid receptor modulators (SGRMs).

We investigated the ability of SGRMs to exert anti-inflammatory effects and to upregulate expression of dual specificity phosphatase 1 (DUSP1), a putative mediator of anti-inflammatory effects of GCs. Although SGRMs were relatively poor activators of a GRE reporter construct, they were able to increase the expression of DUSP1 in different human and murine cell types. The efficacy and potency of this induction varied with cell type and context (absence or presence of a pro-inflammatory stimulus). Moreover, we established a strong correlation between the capacity of GR ligands to induce DUSP1 and their ability to inhibit the expression of the inflammatory mediator cyclooxygenase 2 (COX-2). In conclusion: 1) simplified reporter constructs may not be a reliable guide to the transactivation properties of SGRMs at endogenous GC-responsive genes; 2) transactivation properties of SGRMs may be modulated in a cell type- or context-dependent manner and 3) therapeutic effects of SGRMs may be partly dependent on the upregulation of anti-inflammatory effectors such as DUSP1.