Thymus-derived glucocorticoids are insufficient for normal thymus homeostasis in the adult mouse

Abstract

BackgroundIt is unclear if thymus-derived glucocorticoids reach sufficient local concentrations to support normal thymus homeostasis, or if adrenal-derived glucocorticoids from the circulation are required. Modern approaches to this issue (transgenic mice that under or over express glucocorticoid receptor in the thymus) have yielded irreconcilably contradictory results, suggesting fundamental problems with one or more the transgenic mouse strains used. In the present study, a more direct approach was used, in which mice were adrenalectomized with or without restoration of circulating corticosterone using timed release pellets. Reversal of the increased number of thymocytes caused by adrenalectomy following restoration of physiological corticosterone concentrations would indicate that corticosterone is the major adrenal product involved in thymic homeostasis.ResultsA clear relationship was observed between systemic corticosterone concentration, thymus cell number, and percentage of apoptotic thymocytes. Physiological concentrations of corticosterone in adrenalectomized mice restored thymus cell number to normal values and revealed differential sensitivity of thymocyte subpopulations to physiological and stress-inducible corticosterone concentrations.ConclusionThis indicates that thymus-derived glucocorticoids are not sufficient to maintain normal levels of death by neglect in the thymus, but that apoptosis and possibly other mechanisms induced by physiological, non stress-induced levels of adrenal-derived corticosterone are responsible for keeping the total number of thymocytes within the normal range.

Dysregulation of T-Cell Development in Adrenal Glucocorticoid-Deprived Rats

“…The increased thymic weight and the organ hypercellularity in Adx rats are consistent with data showing that adrenalectomy in mice, or injection of an antagonist of GR (RU486), increases both the thymic size and the thymocyte number (45)(46)(47). This is in keeping with the finding that adrenalectomy in transgenic rats overexpressing a mutant GR with increased ligand affinity, restores the dramatically reduced thymocyte numbers (48).…”

Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic–pituitary–adrenal axis

“…For corticosterone replacement in ADX animal, rats were implanted with 35-mg tablets and mice were implanted subcutaneously with 1.5-mg tablets, both of which are known to produce low physiological levels of corticosterone ( Kovács et al, 2000 ; Pruett and Padgett, 2004 ). Animals were maintained with 0.9% saline drinking water and allowed to recover at least 1 wk before cannula implantation.…”

A In Vitro and In Vivo Study of the Ability of NOD1 Ligands to Activate the Transcriptional Factor NF-kB

“…In order to compare the parameters of the NF-kB activation that is observed upon the introduction of iE-DAP-C12, we selected LPS, the ligand of the Toll-like receptor that has been best studied under in vivo conditions [ 13 , 15 , 16 ].…”