Granulocyte macrophage-colony stimulating factor delays neutrophil apoptosis and primes its function through Ia-type phosphoinositide 3-kinase.
Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases that regulate an array of fundamental cellular responses by neutrophils [polymorphonuclear leukocytes (PMN)]. p85alpha Gene-disrupted mice were used to help accurately identify the physiological role of the PI3K isoform in PMN activation in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF). PMN from the p85alpha-/- mice showed normal cellular motility, and the quantity of superoxide anion (O(2(-))) produced by PMN upon stimulation with formyl-Met-Leu-Phe did not significantly differ between p85alpha-/- and wild-type mice under controlled conditions. In p85alpha-/- mice, the O(2(-)) production by PMN was enhanced (primed) by GM-CSF when stimulated with the chemotactic peptide but to a significantly lesser extent than in wild-type mice. In addition, no major GM-CSF-dependent delay in apoptosis or activation of Akt protein phosphorylation by GM-CSF was observed in the p85alpha-/- mice. In terms of targeting strategy, however, the mutation actually expressed a small amount of Ia-type (p85alpha-regulated) PI3K activity (partially abrogated) in the mice. These results demonstrate that Ia-type PI3K plays a critical role in the enhancement of the GM-CSF-modulated function of PMN and in the PI3K/Akt pathway-dependent delay of PMN apoptosis.
Yasui
Kozo
K
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan. k-yasui@hsp.md.shinshu-u.ac.jp
Sekiguchi
Yukio
Y
Ichikawa
Motoki
M
Nagumo
Haruo
H
Yamazaki
Takashi
T
Komiyama
Atsushi
A
Suzuki
Harumi
H
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013481:Superoxides / Q000378:metabolism
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013481:Superoxides