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

T. Adachi, B. K. Choudhury, S. Stafford, S. Sur, R. Alam

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Abstract

The activation of eosinophils by cytokines is a major event in the pathogenesis of allergic diseases. We have investigated the activation of mitogen-activated protein (MAP) kinases and their functional relevance in eosinophil differentiation, survival, degranulation, and cytokine production. IL-5 induced phosphorylation and activation of extracellular signal-regulated kinases (ERK) and p38 MAP kinases in eosinophils. PD98059, a MAP/ERK kinase inhibitor, blocked phosphorylation of ERK1/2 in a dose-dependent manner. SB202190, a p38 inhibitor, blocked p38-dependent phosphorylation of activating transcription factor-2. To study the importance of the MAP kinases on eosinophil differentiation, we cultured mouse bone marrow cells with IL-3 and IL-5 in the presence of the inhibitors. SB202190 dramatically inhibited eosinophil differentiation by 71%. PD98059 was less potent and reduced eosinophil differentiation by 28%. Both inhibitors marginally inhibited eosinophil survival only at the highest doses. Prolonged incubation of eosinophils with IL-5 induced significant eosinophil-derived neurotoxin release. Both PD98059 and SB202190 nearly completely inhibited (87% and 100% inhibition, respectively) IL-5-stimulated eosinophil-derived neurotoxin release in a dose-dependent manner. Next, we examined the effect of the MAP kinase inhibitors on eosinophil production of the cytokine macrophage- inflammatory protein (MIP)-1α. PD98059 blocked C5a- but not ionomycin- induced MIP-1α production (59% inhibition at 50 μM concentration). In contrast, SB202190 nearly completely inhibited (99%) C5a-induced MIP-1α 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 differentiation, cytokine production, and degranulation. The p38 MAP kinase plays a greater role than ERK1/2 in eosinophil differentiation and cytokine production.

Original languageEnglish (US)
Pages (from-to)2198-2204
Number of pages7
JournalJournal of Immunology
Volume165
Issue number4
DOIs
StatePublished - Aug 15 2000

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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