INTERLEUKIN 8-STIMULATED PHOSPHATIDYLINOSITOL-3-KINASE ACTIVITY REGULATES THE MIGRATION OF HUMAN NEUTROPHILS INDEPENDENT OF EXTRACELLULAR SIGNAL-REGULATED KINASE AND P38 MITOGEN-ACTIVATED PROTEIN-KINASES

Chemoattractants and chemokines, such as interleukin 8 (IL-8), are def ined by their ability to induce directed cell migration of responsive cells, The signal transduction pathway(s) leading to cell migration re main ill defined, We demonstrate that phosphatidylinositol-3-kinase (P I3K) activity, as determined by inhibition using wortmannin and LY2940 02, is required for IL-8-induced cell migration of human neutrophils, Recently we reported that IL-8 caused the activation of the Ras/Raf/ex tracellular signal-regulated kinase (ERK) pathway in human neutrophils and that this activation was dependent on PI3K activity, The regulati on of cell migration by IL-8 is independent of ERK kinase and ERK acti vation since the ERK kinase inhibitor PD098059 had no effect on IL-8-i nduced cell migration of human neutrophils, Additionally, activation o f p38-mitogen-activated protein kinase is insufficient and activation of c-Jun N-terminal kinase is unnecessary to induce cell migration of human neutrophils. Therefore, regulation of neutrophil migration appea rs to be largely independent of the activation of the mitogen-activate d protein kinases, The data argue that PI3K activity plays a central r ole in multiple signal transduction pathways within the human neutroph il leading to distinct cell functions.