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(Journal of Leukocyte Biology. 2002;72:1020-1026.)
© 2002 by Society for Leukocyte Biology

Granulocyte macrophage-colony stimulating factor delays neutrophil apoptosis and primes its function through Ia-type phosphoinositide 3-kinase

Kozo Yasui^*, Yukio Sekiguchi^*, Motoki Ichikawa^*, Haruo Nagumo^*, Takashi Yamazaki^*, Atsushi Komiyama^* and Harumi Suzuki

^* Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan; and
Department of Microbiology and Immunology, Yamaguchi University School of Medicine, Japan

Correspondence: Kozo Yasui, M.D., Ph.D., Department of Pediatrics, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. E-mail: k-yasui{at}hsp.md.shinshu-u.ac.jp

Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases that regulate an array of fundamental cellular responses by neutrophils [polymorphonuclear leukocytes (PMN)]. p85 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 p85-/- 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 p85-/- and wild-type mice under controlled conditions. In p85-/- 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 p85-/- mice. In terms of targeting strategy, however, the mutation actually expressed a small amount of Ia-type (p85-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.

Key Words: rodent • knockout • signal transduction • cytokines

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