Role of caspases in dexamethasone-induced apoptosis and activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase in human eosinophils

Eosinophils are the principal effector cells for the pathogenesis of allerg ic inflammation. Glucocorticoids such as dexamethasone have long been used therapeutically for eosinophilia in allergic inflammation by inducing eosin ophil apoptosis, but little is known about the intracellular mechanisms med iating dexamethasone-induced apoptosis. In the present study, we investigat ed the effect of dexamethasone on three mitogen-activated protein kinases ( MAPK) involved in the intracellular signalling pathway: c-Jun NH2-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK). We found that dexamethasone could activate JNK and p38 MAPK in a time-dependen t manner but not ERK. Further. SE 203580, a specific: p38 MAPK inhibitor, w as additive with dexamethasone in inducing eosinophil apoptosis, while JNK1 /2 antisense phosphorothioate oligodeoxynucleotides did not show any signif icant effect. These suggest that dexamethasone-induced JNK1/2 and p38 MAPK activation are not crucial to the induction of apoptosis. Pretreatment of e osinophils with benzyloxycarbonyl-Val-Ala-Asp-fluoromethy (Z-VAD.FMK), a br oad-spectrum caspase inhibitor, could inhibit dexamethasone-induced apoptos is in eosinophils dose-dependently. Moreover, Z-VAD.FMK partially inhibited dexamethasone-activated JNK and p38 MAPK activities. However, dexamethason e treatment did not activate specific caspase-3, -8 activity in eosinophils compared with spontaneous apoptosis. We therefore conclude that dexamethas one-induced apoptosis and activation of JNK and p38 MAPK activity in eosino phils an regulated by caspases but not through the common apoptosis-related caspase-3, -8 as in other cell types. Elucidation of the important role of caspases in eosinophil apoptosis may facilitate the development of more sp ecific and effective treatment for allergic inflammation.