Structure-activity relationships in glucocorticoid-induced apoptosis in T lymphocytes.
Glucocorticoid-induced apoptosis in the murine interleukin-2-dependent T-cell line CTLL-2 and in freshly isolated thymocytes was studied. It was demonstrated here that in CTLL-2 cells, dexamethasone (methyl in position 16 alpha) was more efficient in inducing apoptosis than betamethasone (methyl in position 16 beta) or triamcinolone (hydroxyl in position 16). In contrast, no such difference between these three molecules was found in murine thymocytes. In addition, we showed that glucocorticoid-induced apoptosis on the two models was mediated through interaction with the glucocorticoid receptor and did not occur in the presence of inhibitors of transcription, translation or an endonuclease-inhibitor. Furthermore, in CTLL-2 cells, apoptosis took place in the presence of EGTA whereas it was prevented in murine thymocytes, thus indicating that calcium plays a different role in these two models. Finally, higher concentrations of interleukin-2 were needed to protect CTLL-2 cells against dexamethasone-induced apoptosis than that induced by betamethasone or triamcinolone. Thus, structural differences at position 16 of the steroid nucleus correlate with a different apoptosis-inducing activity by glucocorticoids which, however, is only evidenced in the calcium-independent CTLL-2 model.
Perrin-Wolff
M
M
Laboratoire d'Immunotoxicologie, Faculté de Pharmacie Paris XI, Châtenay Malabry, France.
Bertoglio
J
J
Bressac
B
B
Bohuon
C
C
Pallardy
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001623:Betamethasone / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000187:drug effects; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D014221:Triamcinolone / Q000737:chemistry / Q000494:pharmacology*
D007376:Interleukin-2; D014221:Triamcinolone; D003907:Dexamethasone; D004247:DNA; D001623:Betamethasone