Dexamethasone-induced apoptosis of mouse thymocytes: prevention by native 7alpha-hydroxysteroids.
Dehydroepiandrosterone (DHEA) has been shown to decrease the dexamethasone (DEX)-induced apoptosis of thymocytes and to be one of the native 3beta-hydroxysteroids extensively 7alpha-hydroxylated in thymus. This led us to question whether DHEA or 7alpha-hydroxy-DHEA is responsible for the decrease in DEX-induced apoptosis of thymocytes and whether this property is shared with other native 3beta-hydroxysteroids and their 7alpha-hydroxylated metabolites. Treatment of mice with DHEA or 7alpha-hydroxy-DHEA prior to DEX led to a smaller decrease in thymus weight than with DEX alone and to a disappearance of the DEX-induced changes in thymocyte phenotypes. Thymocyte apoptosis induced by DEX treatment was significantly lowered in DHEA- and 7alpha-hydroxy-DHEA-treated thymi, even after 18 h culture with additional 10-6 mol/L DEX. Extensive apoptosis of thymocytes cultured with 10-7 mol/L DEX was brought back to control levels when 10-5 mol/L 7alpha-hydroxy-DHEA or 10-5 mol/L 7alpha-hydroxy-epiandrosterone was added. After use of DHEA and epiandrosterone or pregnenolone, less significant and no significant changes were obtained, respectively. These findings imply that the 7alpha-hydroxylation of 3beta-hydroxysteroids may be a prerequisite for an exquisite regulation of the thymocyte-positive selection driven by the glucocorticoids produced in thymic epithelial cells.
Chmielewski
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Laboratoire de Biologie, Conservatoire National des Arts et Métiers, Paris and Laboratoire d'Immunologie, Centre Médico-Chirurgical Foch, Suresnes, France.
Drupt
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Morfin
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D000738:Androsterone / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000494:pharmacology; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006914:Hydroxysteroids / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D011284:Pregnenolone / Q000378:metabolism / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D002250:Carbon Radioisotopes; D006914:Hydroxysteroids; D003687:Dehydroepiandrosterone; D011284:Pregnenolone; D003907:Dexamethasone; D000738:Androsterone