Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria-mediated cell death in TCR- and dexamethasone-stimulatedthymocytes

Mitochondria play a central role in many apoptotic reactions. Although, mit ochondrial apoptotic changes and caspase activation have been demonstrated in the apoptotic thymocytes, cell death signal through mitochondria in TCR- stimulated thymocytes has not been fully understood. In this study, we show that TCR stimulation induced disruption of mitochondrial transmembrane pot ential (Delta Psi (m)), the cytochrome c release from mitochondira, capase- 3 activation, and the cell death of thymocytes. Bongkrekic acid, an inhibit or of Delta Psi (m) disruption, blocked the cytochrome c release from mitoc hondria and the following caspase-3-mediated cell death. Furthermore, a pro -apoptotic Bcl-2 family protein, Bax, but not Bad or Bid, was translocated from cytosol to mitochondria in TOR-stimulated thymocytes. This translocati on and the following apoptotic changes were inhibited by SB203580, a p38 ki nase inhibitor, in a specific manner. These results suggest that activated p38 kinase pathway by TCR stimulation induces translocation of Bax to mitoc hondria, causing Delta Psi (m), disruption, and the release of cytochrome c , which finally induces caspase-3-mediated apoptosis in thymocytes.