Open AccessDeactivation of phosphatidylinositol 3,4,5-trisphosphate/Akt signaling mediates neutrophil spontaneous death
Author(s) -
Daocheng Zhu,
Hidenori Hattori,
Hakryul Jo,
Yonghui Jia,
Kulandayan K. Subramanian,
Fabien Loison,
Jian You,
Yi Liu,
Marek Honczarenko,
Leslie E. Silberstein,
Hongbo R. Luo
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0605722103
Subject(s) - protein kinase b , programmed cell death , phosphatidylinositol , microbiology and biotechnology , pi3k/akt/mtor pathway , apoptosis , biology , pten , signal transduction , inflammation , kinase , cancer research , immunology , biochemistry
Neutrophil spontaneous death plays essential roles in neutrophil homeostasis and resolution of inflammation, whereas the underlying molecular mechanisms are still ill-defined. Neutrophils die because of programmed cell death or apoptosis. However, treatment with inhibitor of caspases, which are responsible for the majority of apoptotic cell deaths, does not prevent the spontaneous death of neutrophils. PKB/Akt possesses prosurvival and antiapoptotic activities in a variety of cells. In this study, we show that Akt activity decreases dramatically during the course of neutrophil death. Both phosphatidylinositol 3-kinase and Akt inhibitors enhance neutrophil death. Conditions delaying neutrophil death, such as treatment with granulocyte–macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or IFN-γ, restore Akt activity. Finally, we demonstrate that neutrophils depleted of PTEN, a phosphatidylinositol 3′-phosphatase that negatively regulates Akt activity, live much longer than WT neutrophils. Thus, we establish Akt deactivation as a causal mediator of neutrophil spontaneous death.