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-Dependent Pathway1
* Department of Immunology/Microbiology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612; and
Department of Dermatology, University of Utah, Salt Lake City, UT 84132
Eosinophil major basic protein (MBP) is an effective stimulus for neutrophil superoxide (O2-) production, degranulation, and IL-8 production. In this study we evaluated the participation of phosphoinositide 3-kinase (PI3K) and PI3K-associated signaling events in neutrophil activation by MBP. Inhibition of PI3K activity blocked MBP-stimulated O2- production, but not degranulation or IL-8 production. Measurement of Akt phosphorylation at Ser473 and Thr308 confirmed that MBP stimulated PI3K activity and also demonstrated indirectly activation of phosphoinositide-dependent kinase-1 by MBP. Genistein and the Src kinase family inhibitor, 4-amino-5-(4-methyphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, inhibited MBP-stimulated phosphorylation of Akt. 4-Amino-5-(4-methyphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine also inhibited MBP-stimulated O2- production. MBP stimulated phosphorylation and translocation of the p85 subunit of class IA PI3K, but not translocation of the p110
subunit of class IB PI3K, to the neutrophil membrane. Inhibition of protein kinase C
(PKC) inhibited MBP-stimulated O2- production. Measurement of phosphorylated PKC (Thr410) and PKC
(Thr505) confirmed that PKC, but not PKC, is activated in MBP-stimulated neutrophils. The time courses for phosphorylation and translocation of the p85 subunit of class IA PI3K, activation of Akt, and activation of PKC were similar. Moreover, inhibition of PI3K activity inhibited MBP-induced activation of PKC. We conclude that MBP stimulates a Src kinase-dependent activation of class IA PI3K and, in turn, activation of PKC in neutrophils, which contributes to the activation of NADPH oxidase and the resultant O2- production in response to MBP stimulation.
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