The role of glucocorticoids sensitivity in immunopathology

Abstract

Glucocorticoids are steroid hormones secreted from the adrenal glands that have important physiological roles in the regulation of basal homeostasis and adaptative response to physical and psychological stress. In particular, glucocorticoids modulate immune function and have been extensively used in clinical practice due to its potent anti-inflammatory and immunosuppressive action. These effects are generally mediated through glucocorticoid receptors expressed on immune cells. Glucocorticoid signaling depends largely on nuclear translocation and association of a hormone-bound GR dimer to specific DNA sequence modulating target gene expression. Glucocorticoids are crucial drugs for the treatment of allergic, inflammatory, autoimmune and lymphoproliferative diseases. However, there are a substantial proportion of patients that do not adequately respond to glucocorticoid therapy. Glucocorticoid resistance has been found mainly in rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma and immune thrombocytopenia. The biologic effects of glucocorticoids are determined by not only their concentrations but also individual and tissue sensitivity to the hormone. In general, glucocorticoid sensitivity refers to the response of a glucocorticoid-responsive system to different concentration of hormone and it is dependent of glucocorticoid receptor expression and affinity and many intracellular mediators that can regulate the signal transduction cascade. Glucocorticoid sensitivity can be modulated by genetic and acquired disease-related factors. Here, we review the mechanism participating in altered glucocorticoid sensitivity that in turn affects their effect on immune response. Specially, we described the participation of changes in receptor expression, glucocorticoid receptor splice variant, functional genetic variants of the glucocorticoid receptor gene, alterations in glucocorticoids receptor signaling and interactions with pro-inflammatory transcription factors. Possible strategies to modulate glucocorticoid sensitivity and improve glucocorticoid therapy are also briefly discussed.