Glucocorticoids (GCs) constitute the most important and widely prescribed class of anti-inflammatory and immunosuppressive drugs. Since their first clinical use more than half a century ago, they have been employed for therapeutic treatment in a variety of diseases such as atopic disorders, autoimmune diseases and cancer. Their efficacy is related to their capability to reduce the expression and activity of many pro-inflammatory agents, that is named “transrepression”. Unfortunately, they also induce serious adverse effects, in particular upon high dosage and prolonged usage, many of which are due to the transcription of genes involved in metabolic processes, that is called “transactivation”. This discrepancy is the driving force for discovery of novel safer GC receptor ligands, such as selective GCs receptor agonists (SEGRAs) able to induce transrepression, whilst avoiding transactivation. The aim of this review is to give an overview of the above-mentioned mechanisms at the basis of GCs action and to summarize the results obtained with SEGRAs in terms of efficacy versus side effects and discuss the opportunities and challenges that this class of ligands might offer for clinical arena.
Keywords: Glucocorticoids, transactivation, transrepression, selective glucocorticoid receptor agonists, immunosuppressive drugs, atopic disorders, autoimmune diseases, cancer, pro-inflammatory agents, transcription, GC receptor ligands, SEGRAs, steroid, Hodgkin's lymphoma, corticosteroids, hydrocortisone, cortisol, prednisolone, methylprednisolone, mineralcorticoid, fluorinated dexamethasone, betamethasone compounds, rheumatic diseases, immune system, osteoporosis, skin atrophy, cushingoid appearance, glaucoma, immunosuppression, GCs effects, osteoblasts, osteocytes, hypothalamic neurons, corticotrophin releasing factor, pituitary corticotroph, hypothalamus-pituitary-adrenal-axis, hyperplasia, DNA-binding domain, ligand-binding domain, zinc-finger motifs, glucocorticoid response element, mitogen-activated protein kinase, hydroxysteroid dehydrogenase, SRC-1, DNA sequences, Cytosolic GR, Immunostimulation, TCR signaling, lymphocyte-specific kinase, glutaminsynthetase, ZK-216348, adrenocorticotropic hormone, osteoprotegerin, PF-4171327, PF-251802