Eosinophils are the principal effector cells for the pathogenesis of allergic
inflammation.
Glucocorticoids such as
dexamethasone have long been used therapeutically for
eosinophilia in allergic
inflammation by inducing eosinophil apoptosis, but little is known about the intracellular mechanisms mediating
dexamethasone-induced apoptosis. In the present study, we investigated 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-dependent manner but not ERK. Further,
SB 203580, a specific
p38 MAPK inhibitor, was additive with
dexamethasone in inducing eosinophil apoptosis, while JNK1/2 antisense phosphorothioate
oligodeoxynucleotides did not show any significant effect. These suggest that
dexamethasone-induced JNK1/2 and
p38 MAPK activation are not crucial to the induction of apoptosis. Pretreatment of eosinophils with
benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (
Z-VAD.FMK), a broad-spectrum
caspase inhibitor, could inhibit
dexamethasone-induced apoptosis in eosinophils dose-dependently. Moreover,
Z-VAD.FMK partially inhibited
dexamethasone-activated JNK and
p38 MAPK activities. However,
dexamethasone treatment did not activate specific
caspase-3, -8 activity in eosinophils compared with spontaneous apoptosis. We therefore conclude that
dexamethasone-induced apoptosis and activation of JNK and
p38 MAPK activity in eosinophils are 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 specific and effective treatment for allergic
inflammation.