Molecular mechanisms of glucocorticoid action: what is important?

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Abstract
Therapeutically, the ability to suppress a number of inflammatory indices makes glucocorticoids among the most potent anti-inflammatory agents currently available for the treatment of chronic inflammatory diseases such as asthma.2 , 3 The clinical efficacy of synthetic glucocorticoids such as prednisolone or dexamethasone stems from their ability to mimic natural glucocorticosteroids. Bodily insults, including inflammation, pain, infection or even mental stress, lead to activation of the hypothalamic-pituitary-adrenal (HPA) axis. These stimuli cause excitation of the hypothalamus, which responds by releasing corticotropin releasing hormone (CRH) (also known as corticotropin releasing factor, CRF). CRH then acts on the anterior pituitary to induce synthesis and release of adrenocorticotropic hormone (ACTH). ACTH in turn stimulates the adrenal cortex to release glucocorticoids such as cortisol. Once within the blood, cortisol is transported to target organs where it elicits numerous metabolic effects including increased blood glucose levels, stimulation of gluconeogenesis in the liver, and the mobilisation of both amino and fatty acids (fig 1). However, in addition to these metabolic effects, glucocorticoids are also potent endogenous immunological suppressors. Thus, whilst the anti-inflammatory power of synthetic glucocorticoids derives from endogenous anti-inflammatory mechanisms, the clinical usefulness of these drugs is limited by HPA insufficiency and effects on bone metabolism in addition to the metabolic effects listed above. In this respect, it is often stated that the metabolic effects of glucocorticoids result from increased transcription of genes such as tyrosine aminotransferase (TAT) and phoshoenolpyruvate carboxykinase (PEPCK),10-13whereas the anti-inflammatory properties are attributed to negative transcriptional effects on inflammatory gene expression.12-14 However, this may not wholly be the case.