ESPE Abstracts (2018) 89 S6.2

Immune Regulation by Glucocorticoids

David Ray

University of Oxford, Oxford, UK

Glucocorticoids (cortisol in humans, corticosterone in rodents) are critical regulators of energy metabolism and immunity. Their secretion by the adrenal gland follows a circadian pattern, with serum concentrations peaking before the active phase (day in humans, night in rodents). Synthetic glucocorticoids are the most potent anti-inflammatory agents known, and are widely used therapeutically, with >1% of the UK population holding a prescription long-term. However, frequent therapeutic use is accompanied by development of severe side effects notably fat accumulation, hyperglycaemia, and hepatosteatosis. Inactive GR is bound by ligand in the cytoplasm and undergoes nuclear translocation, where it binds glucocorticoid response elements (GREs) in the genome to either enhance, or repress gene transcription. Mechanisms to explain how the same molecule can drive gene activation or repression remain under investigation, but likely require an allosteric change induced by DNA target sequence, and/or co-binding with other transcription factors. For gene activation, homodimeric GR recruits co-activator molecules including steroid receptor co-activators (SRC1-3), and histone acetyltransferases (CBP/p300). In contrast, gene repression in the context of anti-inflammation is more complex, with multiple mechanisms of action proposed. Publications report that activated GR binds to, and inhibits the transactivation function of proinflammatory transcription factors, notably the RelA component of the NFkB complex. This was suggested to require recruitment of a co-repressor protein, such as the SRC2 co-modulator. This tethering mechanism explains the lack of consensus GR binding sites in the regulatory regions of inflammatory genes, with the mode of action for GR being to bind to DNA-bound NFkB. However, an alternative mechanism of action has also been proposed, which does not require GR recruitment to the inflammatory genes at all. Here, GR is proposed to act in a conventional manner, to transactivate genes that themselves have anti-inflammatory actions. These include TNFAIP3, DUSP1, and IkB. The protein products of these genes are proposed to act directly on components of NFkB, thereby opposing recruitment to target genes, and thereby interrupting gene activation. The translational implications of uncertainty likely underpin the difficulties in harnessing the anti-inflammatory power of glucocorticoids in the absence of metabolic off-target effects. While some selective glucocorticoid receptor agonists (SeGRMs) have been developed they are struggling in the clinic. However, an orally-active, and selective GR ligand would have potential to transform the management of chronic inflammatory diseases.

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