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CELLULAR AND MOLECULAR

Modulation of Pro- and Antiapoptotic Molecules in Double-Positive (CD4⁺CD8⁺) Thymocytes following Dexamethasone Treatment

Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Tossicologia e Chemioterapia, Università di Perugia Illes Balears Innovació Tecnològica Foundation and Polo Scientifico e Didattico di Terni, Perugia, Italy (R.B., G.N., L.T.K., K.F., S.R., C.R.); and Dipartimento di Medicina Interna, Università degli Studi di Perugia, Azienda Ospedaliera Santa Maria, Perugia, Italy (S.C.)

Glucocorticoids play a role in regulation of T lymphocytes homeostasis and development. In particular, glucocorticoid treatment induces massive apoptosis of CD4⁺CD8⁺ double-positive (DP) thymocytes. This effect is due to many mechanisms, mainly driven by modulation of gene transcription. To find out which genes are modulated, we analyzed DP thymocytes treated for 3 h with dexamethasone (a synthetic glucocorticoid) by global gene expression profiling. Results indicate modulation of 163 genes, also confirmed by either RNase protection assay or real-time polymerase chain reaction. In particular, dexamethasone caused down-regulation of genes promoting DP thymocyte survival (e.g., Notch1, suppressor of cytokine signaling 1, and inhibitor of DNA binding 3) or modulation of genes activating cell death through the ceramide pathway (UDP-glucose ceramide glucosyltransferase, sphingosine 1-phosphate phosphatase, dihydroceramide desaturase, isoform 1, and G protein-coupled receptor 65) or through the mitochondrial machinery. Among the latter, there are Bcl-2 family members (Bim, Bfl-1, Bcl-xL, and Bcl-x), genes involved in the control of redox status (thioredoxin reductase, thioredoxin reductase inhibitor, and NADP⁺-dependent isocitrate dehydrogenase) and genes belonging to Tis11 family that are involved in mRNA stability. Our study suggests that dexamethasone treatment of DP thymocytes modulates several genes belonging to apoptosis-related systems that can contribute to their apoptosis.

Address correspondence to: Carlo Riccardi, Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Università di Perugia, Via del Giochetto, 06122 Perugia, Italy. E-mail: riccardi{at}unipg.it

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