Phorbol myristate acetate induces neutrophil NADPH-oxidase activity by two separate signal transduction pathways: dependent or independent of phosphatidylinositol 3-kinase.
The neutrophil NADPH-oxidase can be activated by protein kinase C (PKC) agonists such as phorbol myristate acetate (PMA), resulting in superoxide anion 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 pools 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 responses were differently affected by the inhibitor Gö-6850, different PKC isozymes are suggested to take part in the two signal transduction pathways.
Karlsson
A
A
Department of Medical Microbiology and Immunology, University of Göteborg, Sweden. anna.karlsson@microbio.gu.se
Nixon
J B
JB
McPhail
L C
LC
D000730:Androstadienes / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008854:Microscopy, Electron; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D054645:Protein Phosphatase 1; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure; D000077191:Wortmannin
D000730:Androstadienes; D006861:Hydrogen Peroxide; D020929:Mitogen-Activated Protein Kinase Kinases; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases; D011493:Protein Kinase C; D054645:Protein Phosphatase 1; D013481:Superoxides; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin