Extra-adrenal glucocorticoid synthesis: immune regulation and aspects on local organ homeostasis

Abstract

Systemic glucocorticoids (GCs) mainly originate from de novo synthesis in the adrenal cortex under the control of the hypothalamus-pituitary-adrenal (HPA)-axis. However, research during the last 1-2 decades has revealed that additional organs express the necessary enzymes and have the capacity for de novo synthesis of biologically active GCs. This includes the thymus, intestine, skin and the brain. Recent research has also revealed that locally synthesized GCs most likely act in a paracrine or autocrine manner and have significant physiological roles in local homeostasis, cell development and immune cell activation. In this review, we summarize the nature, regulation and known physiological roles of extra-adrenal GC synthesis. We specifically focus on the thymus in which GC production (by both developing thymocytes and epithelial cells) has a role in the maintenance of proper immunological function.

Keywords: ACTH; AP-1; CRH; DN; DP; ELISA; Extraadrenal; GCs; GR; Glucocorticoids; HPA-axis; HSD; IFN; IGF-1; IL; LIF; LPS; LRH-1; MAPK; MHC; MLN64; MR; NF-κB; NFAT; PKB; PKC; POMC; SF-1; SP; StAR; Synthesis; T cell differentiation; T cell receptor; TCR; TEC; TLR2; TNF; TNF receptor; TNFR; Thymocyte homeostasis; Thymus; UV; activator protein-1; adrenocorticotropic hormone; corticotrophin-releasing hormone; double negative; double positive; enzyme-linked immunosorbent assay; glucocorticoid receptor; glucocorticoids; hydroxysteroid dehydrogenase; hypothalamic–pituitary–adrenal axis; insulin-like growth factor-1; interferon; interleukin; leukemia inhibitory factor; lipopolysaccharide; liver receptor homolog-1; major histocompatibility complex; metastatic lymph node 64; mineralocorticoid receptor; mitogen activated protein kinase; nuclear factor of activated T cells; nuclear factor κB; pro-opiomelanocortin; protein kinase B; protein kinase C; signal joint T cell receptor excision circles; single positive; sjTREC; steroidogenic acute regulatory protein; steroidogenic factor 1; thymic epithelial cell; toll-like receptor 2; tumor necrosis factor; ultraviolet.