Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice

D'Elia M, Patenaude J, Bernier J. Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice. Am J Physiol Endocrinol Metab 296: E97-E104, 2009. First published November 11, 2008; doi: 10.1152/ajpendo.90582.2008.-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. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 18 beta-glycyrrhetinic acid, a specific 11 beta-HSD inhibitor. Moreover, 11 beta-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-alpha, interleukin (IL)-1 beta, and IL- 6] increased thymocyte sensitivity to DHC-induced apoptosis through a mechanism involving 11 beta-HSD1. Overall, we have shown that burn injury induced 11 beta-HSD1 expression in thymocytes, which led to a greater sensitivity of these cells to CORT-induced apoptosis. Increased expression of 11 beta-HSD1 and GR may play a role in intrathymic T cell development and can be major determinants of GC sensitivity after a trauma.