MODULATION OF SPONTANEOUS AND GLUCOCORTICOID-INDUCED THYMOCYTE APOPTOSIS BU INHIBITORS OF PROTEIN-KINASES

Spontaneous, TCR-driven and glucocorticoid-induced apoptosis of mouse thymocytes are thought to be physiologically modulated by a number of external stimuli which are transduced through receptor-associated prot ein kinases. To investigate the role of cellular kinases in the contro l of apoptotic death of mouse thymocytes, we analyzed the effect of a panel of different protein-kinase inhibitors on in vitro cultured thym ocytes. A protein kinase A inhibitor (KT5720) neither modified the spo ntaneous death of cultured thymocytes, nor reversed the apoptosis prod uced by dexamethasone. The protein kinase C inhibitor H-7 reduced the spontaneous death of thymocytes and abolished the apoptotic effect of dexamethasone. Two other protein kinase C inhibitors (staurosporine an d calphostin-C) enhanced the spontaneous apoptosis of thymocytes but s ignificantly counteracted the DNA fragmentation produced by dexamethas one.-The tyrosine:kinase inhibitor genistein produced a strong reducti on in thymocyte survival through both apoptosis (less than or equal to 100 mu M concentrations) and necrosis (> 100 mu M doses). However, al so in this case, the apoptosis produced by dexamethasone was significa ntly reduced by 100 mu M genistein. Our results confirm that protein k inase C and tyrosine kinase-dependent pathways are important regulator s of both spontaneous and glucocorticoid-induced apoptosis in murine t hymocytes.