The differential role of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in eosinophil functions

The activation of eosinophils by cytokines is a major event in the pathogen esis of allergic diseases. We have investigated the activation of mitogen-a ctivated protein (MAP) kinases and their functional relevance in eosinophil differentiation, survival, degranulation, and cytokine production. IL-5 in duced phosphorylation and activation of extracellular signal-regulated kina ses (ERK) and p38 MAP kinases in eosinophils. PD98059, a MAP/ERK kinase inh ibitor, blocked phosphorylation of ERK1/2 in a dose-dependent manner. SB202 190, a p38 inhibitor, blocked p38-dependent phosphorylation of activating t ranscription factor-2, To study the importance of the MAP kinases on eosino phil differentiation, we cultured mouse bone marrow cells with IL-3 and IL- 5 in the presence of the inhibitors. SB202190 dramatically inhibited eosino phil differentiation by 72%, PD98059 was less potent and reduced eosinophil differentiation by 28%, Both inhibitors marginally inhibited eosinophil su rvival only at the highest doses. Prolonged incubation of eosinophils with IL-5 induced significant eosinophil-derived neurotoxin release. Both PD9805 9 and SB202190 nearly completely inhibited (87% and 100% inhibition, respec tively) IL-5-stimulated eosinophil-derived neurotoxin release in a dose-dep endent manner. Next, we examined the effect of the MAP kinase inhibitors on eosinophil production of the cytokine macrophage-inflammatory protein (MIP )-1 alpha. PD98059 blocked C5a- but not ionomycin-induced MIP-1 alpha produ ction (59% inhibition at 50 mu M concentration). In contrast, SB202190 near ly completely inhibited (99%) C5a-induced MIP-1 alpha production, Further, it blocked ionomycin-stimulated production by 66%, Our results suggest that both p38 and ERK1/2 MAP kinases play an important role in eosinophil diffe rentiation, cytokine production, and degranulation, The p38 MAP kinase play s a greater role than ERK1/2 in eosinophil differentiation and cytokine pro duction.