Biomedical subjects

Domenico Vittorio Delfino

Publications and source records attributed to Domenico Vittorio Delfino.

3 recordsLinked to original sources

PubMed2006

Inhibited cell death, NF-kappaB activity and increased IL-10 in TCR-triggered thymocytes of transgenic mice overexpressing the glucocorticoid-induced protein GILZ.

Glucocorticoids promote thymocyte apoptosis and modulate transcription of several genes including GILZ, which is strongly up-regulated in the thymus. We used transgenic mice overexpressing GILZ in the T-cell lineage to investigate TCR-triggered functions of GILZ-overexpressing thymocytes. TCR-triggered apoptosis, but not glucocorticoid-induced apoptosis, was inhibited in transgenic mice compared to their controls. In vivo anti-CD3 administration did not reduce CD4(+)CD8(+) thymocyte number. Analysis of TCR-triggered molecular changes indicated that p65 NF-kappaB nuclear translocation and DNA binding activity was inhibited in transgenic mice, which might be linked with apoptosis inhibition. IL-10 release increased whereas release of IL-2, IFN-gamma, IL-13 and IL-4 remained unchanged. These results support the hypothesis that GILZ regulates, at least in part, T-cell development by influencing thymus function at cellular and molecular levels.

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PubMed2004

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 GILZ up-regulation was followed by sequential Bcl-xL decreased expression and activation of caspase-8 and of caspase-3. Moreover, GILZ delivered 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 GILZ participates in the regulation of thymocyte apoptosis by glucocorticoids.

Animals↗

PubMed2003

Dexamethasone-induced thymocytes apoptosis requires glucocorticoid receptor nuclear translocation but not mitochondrial membrane potential transition.

Dexamethasone (DEX), a glucocorticoid hormone (GCH) with specificity for the glucocorticoid receptor (GR) induces T lymphocyte and thymocyte apoptosis. DEX-activated thymocyte apoptosis requires a sequence of biochemical events including mRNA and protein synthesis. In particular, GCH treatment induces non-genomic mechanisms, such as for example Ca(2+) mobilization and PI-PLC activation, and genomic mechanisms. Most of these events, including protein synthesis, are required and precede caspase activation. As protein synthesis is required for caspases and apoptosis activation, DEX-induced GR nuclear translocation is necessary for apoptosis. Cell treatment with geldanamycin (GA) inhibits the GR nuclear translocation and consequently, caspases activation and apoptosis. Although DEX treatment induces loss of mitochondrial membrane potential (deltapsim) and cytochrome c release, deltapsim induction does not correlate with thymocyte apoptosis. In fact, while Cyclosporin-A and the caspase-9 inhibitor, Z-LEHD-FMK, inhibit DEX-induced deltapsim, do not influence apoptosis. These data indicate many biochemical events and are activated by DEX treatment of thymocytes and some, but not all, are required for apoptosis.

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