Immune regulation by glucocorticoids

Endogenous and pharmacological glucocorticoids exert robust effects on inflammatory and immune processes. Glucocorticoids receptors are expressed by nearly all cells in the body, yet the effects of glucocorticoids vary by cell type.The production of endogenous glucocorticoids is regulated by the hypothalamic–pituitary–adrenal axis. Glucocorticoids are rapidly induced in response to inflammation and other stressors, but they also follow secretion patterns that are associated with circadian and ultradian rhythms.Glucocorticoids bind cytosolic glucocorticoids receptors, which are ligand-dependent transcription factors. Ligand-bound glucocorticoid receptors regulate gene transcription through three mechanisms: direct binding to DNA via glucocorticoid response elements; protein–protein interactions with other transcription factors; and composite binding to DNA and other transcription factors.Glucocorticoids inhibit inflammation by dampening signal transduction downstream of pattern recognition receptors (PRRs), cytokine receptors and Fcɛ receptors. Glucocorticoids promote the resolution of the inflammatory response through programming effects on macrophages.Glucocorticoids regulate adaptive immunity by inhibiting lymphocyte activation and promoting lymphocyte apoptosis. At high concentrations, glucocorticoids also inhibit the production of B cells and T cells.Glucocorticoid exposure at low doses and/or before challenge can enhance inflammatory responses. Glucocorticoid receptor signalling spares or enhances many pathways that are involved in innate immunity, while suppressing those that are involved in adaptive immunity.We propose that low concentrations of endogenous glucocorticoids sensitize the innate immune system by upregulating PRRs, cytokine receptors and complement factors, thus allowing for rapid responses to danger signals. High concentrations of glucocorticoids, by contrast, suppress signals that are mediated by PRRs and cytokine receptors, thereby preventing excessive and/or prolonged immune responses.