We provide here an unrecognized mechanism how androgens contribute to thymic involution by stimulating local synthesis and release of GCs in the thymus

We provide here an unrecognized mechanism how androgens contribute to thymic involution by stimulating local synthesis and release of GCs in the thymus.Chen, Y., Qiao, S., Tuckermann, J., Okret, S., Jondal, M. here an unrecognized mechanism how androgens contribute to thymic involution by stimulating local synthesis and release of GCs in Gimatecan the thymus.Chen, Y., Qiao, S., Tuckermann, J., Okret, S., Jondal, M. Thymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis. Keywords:testosterone, corticosterone, local glucocorticoid synthesis, glucocorticoid receptor-knockout mice, metyrapone The thymus gland is composed of interdependent stromal and lymphoid compartments, organized into cortical and medullary parts, which promote the Gimatecan differentiation of bone-marrow-derived stem cells into fully immunocompetent naive T cells (1). The progressive loss of these naive recent thymic emigrants (RTEs) into the peripheral T-cell pool as a result of the age-related thymic involution process Gimatecan results in a restricted T-cell repertoire and defects in the cellular immune system in old age (2). This immunosenescence leads to an increased sensitivity to certain clinical conditions, in particular infections, autoimmunity, and possibly cancer in the elderly population (3). An initial loss of thymocytes occurs early in life, at 6 wk of age in mice and at 1 yr of age in humans, and is followed by a more gradual reduction of cells throughout the rest of life (2,4). Although the loss of thymic tissue is usually considerable, the gland retains some functional activity at old age. The cause of thymic involution, which occurs in most vertebrates, is usually unclear but is related to a reduced input of bone-marrow-derived stem cells into the gland, a loss of thymic epithelial cells (TECs), or a combination of both mechanisms (5). However, there is an acceleration of thymic decline after puberty, more pronounced in males compared to in females (6), suggesting that increasing levels of sex hormones contribute to the involution process. Among these hormones, androgens in particular exert considerable influence around the size and composition of the thymus. Exogenous administration of androgens in adult rodents results in an altered cell trafficking, reduced thymocyte proliferation, and an increase in thymocyte apoptosis (7). Conversely, removal of androgen by castration results in thymic enlargement and increased thymopoiesis (8). An enhanced thymic recovery and an increase in peripheral RTEs after bone-marrow transplantation can thus be achieved by physical or chemical castration, consistent with an overall augmented thymopoiesis after withdrawal of androgens (9). Despite the clinical importance, MGC79398 the exact mechanisms by which thymic homeostasis is usually regulated by androgens remain incompletely comprehended. Glucocorticoids (GCs) are steroid hormones that affect a wide range of physiological and pathophysiological processes, including immune responses (10). GCs bind to, and activate, the intracellular GC receptor (GR). The activated receptor complex influences the expression of many genes important for a number of immune functions (10). Increased GC levels, brought on by stress and inflammatory cytokines through the hypothalamus-pituitary-adrenal axis, are anti-inflammatory and immunosuppressive. Increased GC levels also cause thymic involution, which involves a GR-dependent increase in thymocyte apoptosis (10,11). GCs are primarily synthesized in the adrenal glands, but an ectopicde novosynthesis has also been exhibited in the brain, gastrointestinal tract, skin, and thymus (12). In the mouse the major GC is usually corticosterone (CS), derived from cholesterol through the sequential action of steroidogenic acute regulatory protein StAR and the steroidogenic enzymes CYP11A1, 3-HSD, CYP21, and CYP11B1 (13). The tissue expression of 11-HSD1 and 11-HSD2 enzymes, which shuttle the hormone between an active (CS) and an inactive form (11-dehydrocorticosterone), is also important for setting the local GC concentration (13). The initial demonstration of GC synthesis in the thymus was found to occur in TECs and suggested to be important for the T-cell selection process that occurs during thymocyte differentiation (14). More recently, we have shown that thymocytes also synthesize GCs starting from around 4 wk after birth, in contrast to the GC synthesis in TECs, which decline with age (15). We have also found that GC synthesis in thymocytes is usually under the regulation of ACTH and important for the homeostatic regulation of these cells (16). Importantly, by using transgenic mice with an inducible increase in GC sensitivity selectively in thymocytes, we have clearly exhibited that thymus-derived GCs are important in the regulation of thymocyte homeostasis (17). We have proposed that thymocyte-synthesized GCs may contribute.