Glucocorticoid-induced apoptotic pathways in eosinophils: Comparison with glucocorticoid-sensitive leukemia cells

Glucocorticoids are known to promote apoptosis of eosinophils, normal and n eoplastic lymphoid cells, and blastic cells in some patients with acute mye loid leukemia. We investigated the biochemical signal transduction pathways , in particular, the generation of reactive oxygen species (ROS) and activa tion of caspases in dexamethasone (DEX)-induced apoptosis of eosinophils, a nd we compared them with those in DEX-sensitive myeloid and lymphoid leukem ia cell lines. The GC-receptor antagonist completely abolished DEX-induced apoptosis of eosinophils and leukemia cells. Among inhibitors related to th e ROS system, diphenylene iodonium (DPI), a nicotinamide adenine dinucleoti de diphosphate (NADPH) oxidase inhibitor, strongly inhibited both spontaneo us and DEX-induced apoptosis of eosinophils at concentrations as low as 0.2 to 2 mu mol/L, while promoting apoptosis of leukemia cells in a dose-depen dent manner. Apocynin, another NADPH oxidase inhibitor, and antioxidants di d not affect the apoptosis of eosinophils or leukemia cells. DEX treatment did not change intracellular production of O-2(-) and H2O2, and it decrease d the extracellular release of O-2(-) in both cells. These results suggest little or no involvement of ROS generation in DEX-induced apoptosis of both cells. Although among peptide-based caspase inhibitors, only z-VAD-FMK, a broad caspase inhibitor, partially inhibited the apoptosis of eosinophils a nd leukemia cells, DEX treatment increased the activities of caspases 2-, 3 -, 6-, and 8-like proteases assessed by colorimetry in both cells, suggesti ng the involvement of a similar caspase activation pathway in DEX-induced a poptosis in both cells. DPI markedly reduced caspase 3-like activity in eos inophils, while augmenting the activity in leukemia cells, indicating that DPI acts upstream of caspase 3 activation opposingly in both cells. Thus, t he action of DPI in eosinophils seems peculiar in respect to apoptosis indu ction, and DPI appears to exert an influence on unknown targets rather than these involved in NADPH oxidase inhibition. Int J Hematol. 2000;71:340-349 . (C) 2000 The Japanese Society of Hematology.