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Class I_A Phosphatidylinositide 3-Kinases, rather than p110, Regulate Formyl-Methionyl-Leucyl-Phenylalanine-Stimulated Chemotaxis and Superoxide Production in Differentiated Neutrophil-Like PLB-985 Cells¹

Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier de l’Université Laval and Department of Medicine, Faculty of Medicine, Laval University, Sainte-Foy, Québec, Canada

Class I PI3Ks, through the formation of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P₃), are thought of as essential elements of the neutrophil response to chemotactic factors. Moreover, the recent development of PI3K-deficient mice and isoform-specific inhibitors enabled examinations of the contribution of the distinct PI3K isoforms in neutrophil activation. However, the results of these various studies are conflicting, and the exact role of the different PI3K isoforms is not yet clearly established, particularly in human cells. In the present study, we used a different approach to assess the role of the distinct PI3K isoforms in response to the chemotactic agent fMLP. We inhibited PI3K activities by the transient expression following nucleofection of dominant negative mutants of either p85 or p110 in the human myeloid cell line PLB-985, which can be induced to express a neutrophil-like phenotype. The data obtained with this approach showed that the production of PI(3,4,5)P₃ triggered by fMLP is biphasic, with a peak of production observed in a short time period that entirely depends on p110 activity, and a delayed phase that is mediated by class I_A PI3K. We also provide evidence that the PI3K-dependent functional responses (i.e., superoxide production and chemotaxis) induced by the chemotactic factor mainly involve PI3K I_A and, by implication, the delayed phase of PI(3,4,5)P₃ production, whereas p110 and the early peak of PI(3,4,5)P₃ do not play major roles in the initiation or the control of these responses.

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