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Granulocyte-Macrophage Colony-Stimulating Factor Delays Neutrophil Constitutive Apoptosis Through Phosphoinositide 3-Kinase and Extracellular Signal-Regulated Kinase Pathways¹

Jon B. Klein^2,*, Madhavi J. Rane^*, Janice A. Scherzer^*, Patricia Y. Coxon^*, Ralph Kettritz, Jeanine M. Mathiesen^*, Abdul Buridi^* and Kenneth R. McLeish^*,

^* Kidney Disease Program and Department of Biochemistry and Molecular Biology, University of Louisville and Veterans Affairs Medical Center, Louisville, KY 40292; and Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Virchow-Klinikum-Charité, Humboldt University of Berlin, Berlin, Germany

Activated neutrophils play an important role in the pathogenesis of sepsis, glomerulonephritis, acute renal failure, and other inflammatory processes. The resolution of neutrophil-induced inflammation relies, in large part, on removal of apoptotic neutrophils. Neutrophils are constitutively committed to apoptosis, but inflammatory mediators, such as GM-CSF, slow neutrophil apoptosis by incompletely understood mechanisms. We addressed the hypothesis that GM-CSF delays neutrophil apoptosis by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI 3-kinase) pathways. GM-CSF (20 ng/ml) significantly inhibited neutrophil apoptosis (GM-CSF, 32 vs 65% of cells p < 0.0001). GM-CSF activated the PI 3-kinase/Akt pathway as determined by phosphorylation of Akt and BAD. GM-CSF-dependent Akt and BAD phosphorylation was blocked by the PI 3-kinase inhibitor LY294002. A role for the PI 3-kinase/Akt pathway in GM-CSF-stimulated delay of apoptosis was indicated by the ability of LY294002 to attenuate apoptosis delay. GM-CSF-dependent inhibition of apoptosis was significantly attenuated by PD98059, an ERK pathway inhibitor. LY294002 and PD98059 did not produce additive inhibition of apoptosis delay. To determine whether PI 3-kinase and ERK are used by other ligands that delay neutrophil apoptosis, we examined the role of these pathways in IL-8-induced apoptosis delay. LY294002 blocked IL-8-dependent Akt phosphorylation. PD98059 and LY294002 significantly attenuated IL-8 delay of apoptosis. These results indicate IL-8 and GM-CSF act, in part, to delay neutrophil apoptosis by stimulating PI 3-kinase and ERK-dependent pathways.