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*
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.
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L. E. Kilpatrick, J. Y. Lee, K. M. Haines, D. E. Campbell, K. E. Sullivan, and H. M. Korchak A role for PKC-delta and PI 3-kinase in TNF-alpha -mediated antiapoptotic signaling in the human neutrophil Am J Physiol Cell Physiol, July 1, 2002; 283(1): C48 - C57. [Abstract] [Full Text] [PDF]
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R. Hoontrakoon, H. W. Chu, S. J. Gardai, S. E. Wenzel, P. McDonald, V. A. Fadok, P. M. Henson, and D. L. Bratton Interleukin-15 Inhibits Spontaneous Apoptosis in Human Eosinophils via Autocrine Production of Granulocyte Macrophage-Colony Stimulating Factor and Nuclear Factor-kappa B Activation Am. J. Respir. Cell Mol. Biol., April 1, 2002; 26(4): 404 - 412. [Abstract] [Full Text] [PDF]
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 R. Kooijman, A. Coppens, and E. Hooghe-Peters IGF-I Inhibits Spontaneous Apoptosis in Human Granulocytes Endocrinology, April 1, 2002; 143(4): 1206 - 1212. [Abstract] [Full Text] [PDF]
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Y.-S. Bae, Y. Kim, J. C. Park, P.-G. Suh, and S. H. Ryu The synthetic chemoattractant peptide, Trp-Lys-Tyr-Met-Val-D-Met, enhances monocyte survival via PKC-dependent Akt activation J. Leukoc. Biol., February 1, 2002; 71(2): 329 - 338. [Abstract] [Full Text] [PDF]
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G. Heyer, S. Saba, R. Adamo, W. Rush, G. Soong, A. Cheung, and A. Prince Staphylococcus aureusagr and sarA Functions Are Required for Invasive Infection but Not Inflammatory Responses in the Lung Infect. Immun., January 1, 2002; 70(1): 127 - 133. [Abstract] [Full Text] [PDF]
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E. Nijhuis, J.-W. J Lammers, L. Koenderman, and P. J. Coffer Src kinases regulate PKB activation and modulate cytokine and chemoattractant-controlled neutrophil functioning J. Leukoc. Biol., January 1, 2002; 71(1): 115 - 124. [Abstract] [Full Text] [PDF]
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A. Bouchon, C. Hernandez-Munain, M. Cella, and M. Colonna A Dap12-Mediated Pathway Regulates Expression of Cc Chemokine Receptor 7 and Maturation of Human Dendritic Cells J. Exp. Med., October 15, 2001; 194(8): 1111 - 1122. [Abstract] [Full Text] [PDF]
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M. J. Rane, P. Y. Coxon, D. W. Powell, R. Webster, J. B. Klein, W. Pierce, P. Ping, and K. R. McLeish p38 Kinase-dependent MAPKAPK-2 Activation Functions as 3-Phosphoinositide-dependent Kinase-2 for Akt in Human Neutrophils J. Biol. Chem., January 26, 2001; 276(5): 3517 - 3523. [Abstract] [Full Text] [PDF]
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M. C. Martin, I. Dransfield, C. Haslett, and A. G. Rossi Cyclic AMP Regulation of Neutrophil Apoptosis Occurs via a Novel Protein Kinase A-independent Signaling Pathway J. Biol. Chem., November 21, 2001; 276(48): 45041 - 45050. [Abstract] [Full Text] [PDF]
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