Specificity and sensitivity of glucocorticoid signaling in health and disease.

Endogenous glucocorticoids regulate a variety of physiologic processes and are crucial to the systemic stress response. Glucocorticoid receptors are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and induced biological responses across tissues. The immunoregulatory properties of glucocorticoids are exploited in the clinic for the treatment of inflammatory and autoimmune disorders as well as certain hematological malignancies, but adverse side effects hamper prolonged use. Fully understanding the molecular events that shape the physiologic effects of glucocorticoid treatment will provide insight into optimal glucocorticoid therapies, reliable assessment of glucocorticoid sensitivity in patients, and may advance the development of novel GR agonists that exert immunosuppressive effects while avoiding harmful side effects. In this review, we provide an overview of mechanisms that affect glucocorticoid specificity and sensitivity in health and disease, focusing on the distinct isoforms of the glucocorticoid receptor and their unique regulatory and functional properties.