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.
Highlights
It 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
Recent results indicate that overexpression of glucocorticoid receptors (GR) in developing and mature T cells leads to decreased cell number in the thymus and a decreased number of T cells in the periphery in adult mice
Adrenalectomy increases cell number and alters subpopulation percentages in the thymus, and this effect is inhibited 24 hr after restoration of corticosterone The results shown in Figure 1 demonstrate that adrenalectomy significantly increases the total number of cells in the thymus as well as the number of CD4+CD8- and CD4+CD8+ cells
Summary
It 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. There is convincing evidence that corticosterone is produced in the thymus and that it acts locally to affect thymocyte development [8,9] It was surprising when normal cellular development (including repertoire) was observed until the time of birth in glucocorticoid receptor knockout mice (page number not for citation purposes). One group using transgenic mice that express anti-sense GR mRNA in the thymus found increased thymus cellularity [4], whereas another group using a cre-lox conditional knockout system to eliminate glucocorticoid receptor in cells that express CD4 (including double positive cells) reported no increase in cellularity [14]. Transgenic approaches cannot provide the concentration-response information for corticosterone that would be needed to distinguish normal physiological effects and stress-related effects
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