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Essential Role of Phosphoinositide 3-Kinase in Neutrophil Directional Movement

ICOS Corporation, Bothell, WA 98021

Neutrophil chemotaxis is a critical component of the innate immune response. Neutrophils can sense an extremely shallow gradient of chemoattractants and produce relatively robust chemotactic behavior. This directional migration requires cell polarization with actin polymerization occurring predominantly in the leading edge. Synthesis of phosphatidylinositol (3,4,5) trisphosphate (PIP3) by phosphoinositide 3-kinase (PI3K) contributes to asymmetric F-actin synthesis and cell polarization during neutrophil chemotaxis. To determine the contribution of the hemopoietic cell-restricted PI3K in neutrophil chemotaxis, we have developed a potent and selective PI3K inhibitor, IC87114. IC87114 inhibited polarized morphology of neutrophils, fMLP-stimulated PIP3 production and chemotaxis. Tracking analysis of IC87114-treated neutrophils indicated that PI3K activity was required for the directional component of chemotaxis, but not for random movement. Inhibition of PI3K, however, did not block F-actin synthesis or neutrophil adhesion. These results demonstrate that PI3K can play a selective role in the amplification of PIP3 levels that lead to neutrophil polarization and directional migration.

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