Dexamethasone-induced apoptosis of mouse thymocytes: Prevention by native 7 alpha-hydroxysteroids

Dehydroepiandrosterone (DHEA) has been shown to decrease the dexamethasone (DEX)-induced apoptosis of thymocytes and to be one of the native 3 beta-hy droxystrroids extensively 7 alpha-hydroxylated in thymus. This led us to qu estion whether DHEA or 7 alpha-hydroxy-DHEA is responsible for the decrease in DEX-induced apoptosis of thymocytes and whether this property is shared with other native 3 beta-hydroxysteroids and their 7 alpha-hydroxylated me tabolites. Treatment of mice with DHEA or 7 alpha-hydroxy-DHEA prior to DEX led to a smaller decrease in thymus weight than with DEX alone and to a di sappearance of the DEX-induced changes in thymocyte phenotypes. Thymocyte a poptosis induced by DEX treatment was significantly lowered in DHEA- and 7 alpha-hydroxy-DHEA-treated thymi, even after 18 h culture with additional 1 0(-6)mol/L DES. Extensive apoptosis of thymocytes cultured with 10(-7) mol/ L DEX was brought back to control levels when 10(5) moL/L 7 alpha-hydroxy-D HEA or 10(-5) mol/L 7 alpha-hydroxy-epiandrosterone was added. After use of DI-IEA and epiandrosterone or pregnenolone, less significant and no signif icant changes were obtained, respectively. These findings imply that the 7 alpha-hydroxy-lation of 3 beta-hydroxysteroids may be a prerequisite for an exquisite regulation of the thymocyte-positive selection driven by the glu cocorticoids produced in thymic epithelial cells.