Phorbol myristate acetate induces neutrophil NADPH-oxidase activity by twoseparate signal transduction pathways: dependent or independent of phosphatidylinositol 3-kinase

The neutrophil NADPH-oxidase can be activated by protein kinase C (PKC) ago nists such as phorbol myristate acetate (PMA), resulting in superoxide anio n release. This superoxide release is independent of phosphatidylinositol 3 -kinase (PI 3-kinase) because the inhibitor wortmannin does not affect the response. In this study, PMA is shown to also induce a wortmannin-sensitive NADPH-oxidase activation, however, not resulting in release of superoxide but in intracellular production of the radical. This indicates that two poo ls of NADPH-oxidase, one localized in the plasma membrane and the other in the granule membranes, are separately regulated and the signal transduction pathways leading to activation of these pools differ regarding involvement of PI 3-kinase. Activation of both pools was dependent on ERK/MAPK kinase (MEK) activity and protein phosphatase 1 and/or 2A. As the two oxidase resp onses were differently affected by the inhibitor Go-6850, different PKC iso zymes are suggested to take part in the two signal transduction pathways.