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Published online before print August 24, 2004

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(Journal of Leukocyte Biology. 2004;76:1047-1056.)
© 2004 by Society for Leukocyte Biology

Short-term delay of Fas-stimulated apoptosis by GM-CSF as a result of temporary suppression of FADD recruitment in neutrophils: evidence implicating phosphatidylinositol 3-kinase and MEK1-ERK1/2 pathways downstream of classical protein kinase C

Yasuko Kotone-Miyahara^*, Kouhei Yamashita^*, Kyung-Kwon Lee, Shin Yonehara, Takashi Uchiyama^*, Masataka Sasada and Atsushi Takahashi^*,1

^* Department of Hematology and Oncology, Graduate School of Medicine,
Graduate School of Biostudies, and
College of Medical Technology, Kyoto University, Japan

¹ Correspondence: Division of Hematology and Oncology, Department of Internal Medicine, Kyoto University Hospital, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: atakahashi{at}ca.wakwak.com

Granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibits Fas-induced apoptosis of neutrophils. However, the exact step in the apoptotic pathway blocked by GM-CSF remained unclear. Here, we found that pretreatment of neutrophils with GM-CSF inhibits the recruitment of Fas-associated protein with death domain (FADD) to Fas, abolishing the formation of the death-inducing signaling complex required for Fas-induced apoptosis. Two-dimensional electrophoresis revealed that GM-CSF modifies the ratio of FADD subspecies. These GM-CSF-triggered changes were abrogated, and Fas-induced apoptosis was restored by an inhibitor of classical protein kinase C (PKC), Gö6976, and by the combination of a phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002, and an inhibitor of mitogen-activated protein kinase kinase (MEK)1, PD98059. Gö6976 blocked GM-CSF-elicited phosphorylation of Akt/PKB and extracellular signal-regulated kinase (ERK)1/2. These results indicated that GM-CSF suppresses Fas-induced neutrophil apoptosis by inhibiting FADD binding to Fas, through redundant actions of PI-3K and MEK1-ERK1/2 pathways downstream of classical PKC.

Key Words: death-inducing signaling complex • Gö6976 • LY294002 • PD98059 • caspase-8

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