Abstract
The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit.
Highlights
Glucocorticoids (GCs) are steroid hormones derived from cholesterol and secreted by the adrenal glands
We present data demonstrating an advantageous profile of glucocorticoid receptor (GR) ligand/modulator combinations, more precisely the combination of the full agonist Dexamethasone (DEX) with the selective GR agonists and modulators (SEGRAMs) Compound A (CpdA)
We investigated the functional outcome upon combining the classic GR ligand, DEX, with the GR modulator, CpdA
Summary
Glucocorticoids (GCs) are steroid hormones derived from cholesterol and secreted by the adrenal glands. GCs exert their pleiotropic actions through the glucocorticoid receptor α (GR), a ligand-dependent transcription factor (TF) belonging to the nuclear receptor superfamily[1,2,3]. The GR can interfere with the activities of various pro-inflammatory TFs, including nuclear factor κB (NF-kB), without the necessity of DNA binding[4]. This mechanism, called transrepression, is associated with the well-known anti-inflammatory actions of GR. The therapeutic benefits are overshadowed by the occurrence of deleterious side effects and GC resistance For these reasons, a whole range of so-called selective GR agonists and modulators (SEGRAMs) have been characterized and/or developed, aimed at displaying a more dissociative profile, i.e. favouring GR-mediated transrepression over transactivation. We present data demonstrating an advantageous profile of GR ligand/modulator combinations, more precisely the combination of the full agonist Dexamethasone (DEX) with the SEGRAM CpdA
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