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 betam ethasone (methyl in position 16 beta) or triamcinolone (hydroxyl in po sition 16). In contrast, no such difference between these three molecu les was found in murine thymocytes. In addition, we showed that glucoc orticoid-induced apoptosis on the two models was mediated through inte raction with the glucocorticoid receptor and did not occur in the pres ence of inhibitors of transcription, translation or an endonuclease-in hibitor. Furthermore, in CTLL-2 cells, apoptosis took place in the pre sence of EGTA whereas it was prevented in murine thymocytes, thus indi cating that calcium plays a different role in these two models. Finall y, higher concentrations of interleukin-2 were needed to protect CTLL- 2 cells against dexamethasone-induced apoptosis than that induced by b etamethasone or triamcinolone. Thus, structural differences at positio n 16 of the steroid nucleus correlate with a different apoptosis-induc ing activity by glucocorticoids which, however, is only evidenced in t he calcium-independent CTLL-2 model.