The glucocorticoid receptor as target for classic and novel anti-inflammatory therapy

Glucocorticoids are well known for their potent anti-inflammatory and immune-suppressive actions. Their clinical usefulness remains limited due to serious side effects that have necessitated a search for ways of improving their benefit-risk ratios. Mechanistically, glucocorticoids function by interacting with an intracellular receptor, the glucocorticoid receptor, a ligand-regulated transcription factor that positively or negatively alters the expression of specific genes. While it is well accepted that distinct negative regulatory action of this receptor forms the basis of the desired anti-inflammatory effects of glucocorticoids, not much is known about the function of the receptor that contributes to its side effects. The fact that a number of cellular metabolic control genes are positively regulated by glucocorticoids makes positive regulation of gene expression an attractive mode of action for the adverse effects. Positive regulation of gene expression by glucocorticoids, however, occurs through different mechanisms and in cell-type specific manner making it difficult to predict its possible biological effects in one single assay procedure. Recent advances in the molecular action of the receptor are gradually revealing different assays and important characteristics that can be put together in determining the physiological consequences of the different transactivation functions of the glucocorticoid receptor. These will provide invaluable source of information for the search of glucocorticoid receptor agonists with potent anti-inflammatory but reduced side effects.