ERK1 and ERK2 activation by chemotactic factors in human eosinophils is interleukin 5-dependent and contributes to leukotriene C-4 biosynthesis

Eosinophils, the major immune effector cells contributing to allergic infla mmation and asthma, are profoundly affected by interleukin (IL) 5 with resp ect to their differentiation, viability, recruitment, and cytotoxic effecto r functions. IL-5 enhances eosinophil responsiveness to a variety of chemot actic factors via a process called priming, although the molecular mechanis m is unknown. In this study, we report that, following IL-5 priming of eosi nophils, chemotactic agents including fMet-Leu-Phe, IL-8, and RANTES, promo te vigorous transient activation of ERK1 and ERK2. In contrast, these chemo tactic factors stimulate weak or indiscernible ERK activation in unprimed e osinophils. Furthermore, this intracellular marker of priming is selective for IL-5-related cytokines, in that it is observed following exposure to IL -5 and granulocyte macrophage-colony stimulating factor but not to interfer on-gamma, stem cell factor, tumor necrosis factor alpha, or IL-4, Interesti ngly, priming of chemoattractant-induced ERK activation is accompanied by a n increase in association of tyrosine-phosphorylated proteins with the adap ter protein Grb2, The biological relevance of ERK activation to IL-5 primin g is supported by the observation that inhibition of ERK activity by treatm ent with the MEK inhibitors PD98059 or U0126 inhibited the release of leuko triene C-4 stimulated by fMet-Leu-Phe in IL-5-primed eosinophils, These dat a provide evidence for a previously undescribed fundamental mechanism by wh ich stimulation of IL-5 family receptors induces a rapid phenotypic alterat ion in the signal transduction pathways of chemotactic receptors, enabling their activation of the ERK1 and ERK2 pathway and contributing to the capac ity of these cells to synthesize LTC4.