Control of immunity by glucocorticoids in health and disease

Animals receive environmental stimuli from neural signals in order to produce hormones that control immune responses. Glucocorticoids (GCs) are a group of steroid hormones produced in the adrenal cortex and well-known mediators for the nervous and immune systems. GC secretion is induced by circadian rhythm and stress, and plasma GC levels are high at the active phase of animals and under stress condition. Clinically, GCs are used for allergies, autoimmunity, and chronic inflammation, because they have strong anti-inflammatory effects and induce the apoptosis of lymphocytes. Glucocorticoid receptor (GR) acts as a transcription factor and represses the expression of inflammatory cytokines, chemokines, and prostaglandins by binding to its motif, glucocorticoid-response element, or to other transcription factors. In mice, GR suppresses the antigen-stimulated inflammation mediated by macrophages, dendritic cells, and epithelial cells, and impairs cytotoxic immune responses by downregulating interferon-γ production and inhibiting the development of type-1 helper T cells, CD8+ T cells, and natural killer cells. These immune inhibitory effects prevent lethality by excessive inflammation, but at the same time increase the susceptibility to infection and cancer. GCs can also activate the immune system. The circadian cycle of GC secretion controls the diurnal oscillations of the distribution and response of T cells, thus supporting T cell maintenance and effective immune protection against infection. Moreover, several reports have shown that GR has the potential to enhance the activities of Th2, Th17, and immunoglobulin-producing B cells. Stress has two different effects on immune responses: immune suppression to cause mortality by infection and cancer, and excessive immune activation to induce chronic inflammation and autoimmune disease. Consistently, stress-induced GCs strongly suppress cell-mediated immunity and cause viral infection and tumor development. They may also enhance the development of pathogenic helper T cells and cause tissue damage through neural and intestinal inflammation. Past studies have reported the positive and negative effects of GCs on the immune system. These opposing properties of GCs may regulate the immune balance between the responsiveness to antigens and excessive inflammation in steady-state and stress conditions.