Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice

Abstract

Glucocorticoids (GC) are important steroid hormones that regulate metabolism, development, and the immune system. GC are produced continuously, and maximal levels are reached following stress-related stimuli. Previous studies have demonstrated that increased GC production following thermal injury was responsible for thymic involution. Although GC are mainly synthesized by the adrenal glands, there is increasing evidence that GC may also be produced in nonadrenal tissues. The thymus was reported to express steroidogenic enzymes and to release GC. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is predominantly a reductase in cells and is essential for the local reactivation of GC. Here, we report that increased GC-induced apoptosis in thymocytes from burn-injured mice is related to increased glucocorticoid receptor (GR) expression and 11β-HSD1 expression in thymocytes at day 1 postburn injury. In vitro, thymocytes were able to convert 11-dehydrocorticosterone (DHC) to corticosterone (CORT), which induced their apoptosis, and this was pharmacologically inhibited by 18β-glycyrrhetinic acid, a specific 11β-HSD inhibitor. Moreover, 11β-HSD1 expression was confirmed in the 267S3 thymoma-derived cell line, and its activity was responsible for greater sensitivity of these cells to CORT-induced apoptosis. Finally, proinflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1β, and IL-6] increased thymocyte sensitivity to DHC-induced apoptosis through a mechanism involving 11β-HSD1. Overall, we have shown that burn injury induced 11β-HSD1 expression in thymocytes, which led to a greater sensitivity of these cells to CORT-induced apoptosis. Increased expression of 11β-HSD1 and GR may play a role in intrathymic T cell development and can be major determinants of GC sensitivity after a trauma.

The Effect of Restraint Stress on Glucocorticoid Receptors in Mouse Spleen Lymphocytes: Involvement of the Sympathetic Nervous System

“…This may indicate that stress exposure upregulates splenocyte GRs at the levels of ligand binding and at the level of GR protein expression. These results are in accordance with previous reports showing that stress caused by severe burn injury in mice induced a significant increase in the expression of GRs in thymocytes [31] . Another report also showed increased GR expression in neural and immune tissues following systemic stress [32] .…”

“…At least in thymocytes, such an increase in GR expression may induce greater sensitivity of cells to apoptosis induced by GCs [31,42] .…”

T cells from burn-injured mice demonstrate a loss of sensitivity to glucocorticoids

“…Control samples and cells were treated or not with 100 nM RU-486 (Sigma-Aldrich) a GR inhibitor, 30 min prior to CORT exposition. Following culture, cells were treated as previously described (10), and apoptosis was quantified by flow cytometry on a FACScan flow cytometer (Becton-Dickinson) by measuring the precentage of cells in phase sub-G0/G1.…”

Upregulation of 11β-hydroxysteroid dehydrogenase 1 in lymphoid organs during inflammation in the rat

“…However, it is not currently known whether proinflammatory cytokines alter 11HSDs in the colon or whether inflammation modulates glucocorticoid metabolism in lymphoid organs. Only thermal stress has been recently shown to modulate 11HSD1 expression in thymus [20]. Our objectives in this study were therefore to determine the effect of TNF-␣ and IL-1␤ on colonic 11HSD1 and 2 and to investigate the effect of inflammation associated with colitis on 11HSD1 in the spleen and mesenteric lymph nodes (MLN), i.e.…”