The synthetic chemoattractant peptide WKYMVm induces superoxide production by human eosinophils via the phosphoinositide 3-kinase-mediated activation of ERK1/2.

Eosinophils play a key role in allergic inflammation and parasitic infections. The synthetic peptide, Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), has been previously shown to activate eosinophils and thus to enhance respiratory burst through the formyl peptide receptors. This study was undertaken to determine the intracellular signaling pathway involved in WKYMVm-stimulated superoxide production by human eosinophils. Purified eosinophils from peripheral blood were stimulated with various concentrations (10(-3) to 10 microM) of WKYMVm and the involvement of PI3-kinase and MAP kinases in WKYMVm-triggered superoxide production was investigated using pharmacological inhibitors. WKYMVm-induced superoxide production by eosinophils was strongly inhibited by pretreatment with the PI3-kinase inhibitor LY294002. In addition, pretreatment with the ERK1/2 kinase inhibitor PD98059 resulted in marked inhibition of superoxide production induced by WKYMVm. Indeed, WKYMVm strongly induced phosphorylation of ERK1/2. The ERK1/2 activation by the peptide was transient and peaked after 2 min of stimulation. Furthermore, ERK1/2 activation by WKYMVm was completely inhibited by pretreatment with the PI3-kinase inhibitor LY294002, but not by the PKC inhibitor Ro-31-8220. These results suggest that WKYMVm stimulates human eosinophils to induce superoxide production via a PI3-kinase-mediated ERK1/2 pathway.