Local glucocorticoid synthesis and regeneration in lymphoid organs: Neonatal and adult mice

Abstract

Glucocorticoids are synthesized in the adrenal glands and circulate through the blood to coordinate organismal physiology. In early life, elevated glucocorticoids suppress growth and neural development, and altricial neonates avoid these deleterious effects by undergoing a stress hyporesponsive period during which circulating glucocorticoids are low. However, elevated glucocorticoids may be needed in other tissues, such as the thymus, for their critical role in production of immunocompetent T cells. Here, we show that lymphoid organs increase their local glucocorticoid levels via glucocorticoid production, and that production increases with age. Murine lymphoid organs (thymus, bone marrow, spleen) produced corticosterone in vitro, and this production was blocked by metyrapone, which inhibits both CYP11B1 synthesis of corticosterone from precursors (deoxycorticosterone) and 11beta-HSD1 regeneration of corticosterone from metabolites (dehydrocorticosterone). Gene expression and enzyme activity of 11beta-HSD1 were much higher than expression and activity of CYP11B1, which were extremely low or nondetectable. Adults showed higher 11beta-HSD1 expression and activity than neonates. These findings show that lymphoid organs produce glucocorticoids via regeneration, and that regeneration increases with age. Furthermore, regeneration occurs not only in the thymus, where glucocorticoids are necessary for T cell development, but also in bone marrow and spleen, the sites of B cell development. As developing B cells have high levels of glucocorticoid receptors, locally-produced glucocorticoids likely play a critical role in both T and B cell development.