Thymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis

Abstract

Androgens contribute to the involution process of the aging thymus gland. However, molecular mechanisms behind this effect remain largely unknown. We have investigated the influence of testosterone on the ectopic synthesis of glucocorticoids (GCs) in thymocytes, an activity recently shown by us to be important for the homeostatic regulation of these cells. Castration, which leads to a strong increase in thymus tissue and function, was associated with a reduced GC release from thymocytes caused by down-regulated expression of several enzymes involved in GC synthesis, without affecting GC synthesis in the adrenals. Testosterone treatment of castrated male mice reversed these effects, also without affecting adrenal GC synthesis. The effects of testosterone in castrated mice on thymocyte homeostasis and GC release were strongly reduced in mice pretreated with the CYP11B1 enzyme inhibitor metyrapone, acting on the last step in the corticosterone synthesis. The androgen-induced thymic involution was dependent on GC action, because this was completely absent in mice lacking GC receptor (GR) expression specifically in thymocytes. We provide here an unrecognized mechanism how androgens contribute to thymic involution by stimulating local synthesis and release of GCs in the thymus.

Interpreting Stress Responses during Routine Toxicity Studies

“…The stimulus for progressive involution is preprogrammed and intrinsic to the thymus, and not attributable to emigration of cells from the bone marrow to the thymus (Aspinall 2000;Mackall and Gress 1997). Peripubertal increases in gonadal hormones and decreases in growth hormone promote involution (Chen et al 2010;Sfikakis et al 1998). Local concentrations of glucocorticoids are important for appropriate thymic development and T-lymphocyte development, differentiation, and selection in younger animals (Herold, McPherson, and Reichardt 2006;Jaffe 1924aJaffe , 1924bJaffe , 1924cJondal, Pazirandeh, and Okret 2004;Pazirandeh, Jondal, and Okret 2004;Stojic-Vukanic et al 2009).…”

Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function

“…Thymic epithelial cells also activate GR-mediated transcription in cocultured cells (69). In addition to thymic epithelial cells, thymocytes themselves also express StAR, CYP11A1, 3␤-HSD, CYP17, CYP21, and CYP11B1 mRNA and synthesize corticosterone (10,75,76). Moreover, the chicken thymus contains functional CYP11A1, 3␤-HSD, CYP21, and CYP11B1 enzymes for glucocorticoid synthesis, but the additional presence of CYP17 activity directs synthesis toward cortisol rather than corticosterone, in contrast to the chicken adrenals (46).…”

“…Since the stress-hyporesponsive period coincides with high local synthesis in lymphoid organs, local production may serve to maintain high local glucocorticoid levels in lymphoid organs while systemic levels are low. In contrast to thymic epithelial cells, thymocyte production of glucocorticoids increases at puberty (ϳ4 wk in mice) (75) and is stimulated by testosterone in males (10).…”

Bronchial Epithelial Cells Induce Alternatively Activated Dendritic Cells Dependent on Glucocorticoid Receptor Signaling

“…This indicates that PGE 2 in concert with glucocorticoids suppress proinflammatory cytokines in DCs. Glucocorticoid synthesis occurs in the cortex of the adrenal gland, but extra-adrenal glucocorticoid synthesis has been reported in the murine intestine and pulmonary tissue (45,46) as well as in skin and thymus (47). In murine intestine, de novo synthesis of glucocorticoids is controlled by TNF under inflammatory conditions (48), whereas increased reactivation of inactive glucocorticoids in the lung has been described in the pulmonary system after immune cell stimulation (49).…”