Position 16 of the steroid nucleus modulates glucocorticoid-induced apoptosis at the transcriptional level in murine T-lymphocytes.
Synthetic glucocorticoids (GCs), which possess a different radical substituted in position 16 of the steroid nucleus structure, display various antiproliferative activities on activated lymphoid cells. We analysed this structure-function relationship between dexamethasone (DEX; methyl group in position 16 alpha) and beta-methasone (BM; methyl group in position 16 beta) with regard to two important aspects of GC activity, namely the activation of transcription and induction of apoptosis in IL-2-dependent murine lymphoid cells. DEX induced a higher percentage of apoptotic viable cells compared to BM. This structure-activity relationship was not related to differences in cytosolic glucocorticoid receptor (GR) affinity or kinetics of apoptosis. However, DEX was more efficient than BM in inducing transcriptional activation of an MMTV-CAT plasmid in transiently transfected CTLL-2 cells. In addition, DEX was more potent in inhibiting AP-1 DNA-binding activity compared to BM. These results suggest that the configuration in position 16 may influence the potency of GCs to induce apoptosis in lymphoid cells, mainly by modulating GR-induced transcription.
Perrin-Wolff
M
M
Immunotoxicologie et Cancérogènese, CJF INSERM 93-01 Faculté de Pharmacie Paris-Sud, Châtenay-Malabry, France.
Mishal
Z
Z
Bertoglio
J
J
Pallardy
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001623:Betamethasone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D003907:Dexamethasone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005938:Glucocorticoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D004247:DNA; D001623:Betamethasone