Decrease of Bcl-xL and augmentation of thymocyte apoptosis in GILZ overexpressing transgenic mice

Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous genes. GILZ(glucocorticoid-induced leucine zipper), being one of them, is strongly up-regulated in the thymus. To elucidate its function we generated transgenic mice overexpressing it specifically in the T-cell lineage and characterized its influence on thymus function. In young adult transgenic mice CD4+CD8+thymocyte number was significantly decreased and ex vivo thymocyte apoptosis was increased. Apoptotic pathway analysis detected reduced antiapoptotic B-cell leukemia XL (Bcl-xL) expression and increased activation of caspase-8 and caspase-3. Time-course experiments showed that in wild-type (WT) thymocytes GILZup-regulation was followed by sequential Bcl-xL decreased expression and activation of caspase-8 and of caspase-3. Moreover, GILZdelivered inside WT thymocytes by a fusion protein with the transactivator of transcription (TAT) peptide decreased Bcl-xL and promoted their apoptosis. In aged mice perturbation of thymic subset numbers was amplified over time, as demonstrated by a further decrease in CD4+CD8+cells and increases in CD4+CD8-, CD4-CD8-, and CD8+CD4-cell counts. These results support the hypothesis that GILZparticipates in the regulation of thymocyte apoptosis by glucocorticoids. (Blood. 2004;104:4134-4141)