1. Resistance of single-positive thymocytes to glucocorticoid-induced apoptosis is mediated by CD28 signaling.
- Author
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van den Brandt J, Wang D, and Reichardt HM
- Subjects
- Animals, Apoptosis physiology, CD28 Antigens drug effects, CD28 Antigens genetics, CD4 Antigens drug effects, CD4 Antigens metabolism, Calcium metabolism, Calmodulin metabolism, Cells, Cultured, Dexamethasone pharmacology, Enzyme Inhibitors pharmacology, Gene Expression Regulation drug effects, Membrane Proteins, Mice, Mice, Knockout, Phosphatidylinositol 3-Kinases drug effects, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-bcl-2 drug effects, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Rats, Rats, Inbred Lew, Thymus Gland drug effects, Thymus Gland pathology, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein, Apoptosis drug effects, CD28 Antigens metabolism, Glucocorticoids pharmacology, Thymus Gland metabolism
- Abstract
Glucocorticoids administered in pharmacological doses potently induce apoptosis in immature double-positive thymocytes. In contrast, single-positive thymocytes are completely resistant. We now provide evidence that this difference can be attributed to CD28 signaling. When taken into culture, single-positive thymocytes also become sensitive to glucocorticoid-induced apoptosis, which can be prevented by enforced CD28 engagement using a novel type of antibody. This is achieved, at least in part, by transcriptional regulation of apoptosis-related genes such as Bcl-X(L) via a calcium- and phosphatidylinositol 3 kinase-dependent pathway. Accordingly, deficiency of CD28 in genetically engineered mice leads to an increased sensitivity of single-positive thymocytes toward glucocorticoid-induced cell death in vivo. Taken together, we have identified CD28 signaling in the thymus as a key player in determining the differential sensitivity of double-positive and single-positive cells to glucocorticoid action.
- Published
- 2004
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