Protein-tyrosine phosphorylation regulates apoptosis in human eosinophils and neutrophils.
Early signaling events that control the process of programmed cell death are largely unknown. Tyrosine phosphorylation plays a major role in transmembrane signal transduction through most cell surface receptors. Granulocyte/macrophage colony-stimulating factor (GM-CSF), a cytokine released by activated T cells, has been shown to increase tyrosine phosphorylation in several cells and to inhibit granulocyte cell death in vitro. In this study, we demonstrate that the effect of GM-CSF on granulocyte cell death can be blocked by the tyrosine kinase inhibitor genistein, suggesting that increases in tyrosine phosphorylation are essential to inhibit cell death. To analyze the role of tyrosine phosphorylation for the regulation of granulocyte cell death more precisely, we increased levels of tyrosine phosphorylation using the protein-tyrosine phosphatase inhibitor phenylarsine oxide (PAO). Similar to GM-CSF, treatment of the cells with PAO was followed by high increases in tyrosine phosphorylation and inhibition of programmed cell death in human eosinophils and neutrophils. Strikingly, at low concentrations of the inhibitor and low induction of tyrosine phosphorylation, acceleration of apoptosis was observed. Genistein and herbimycin A reversed the effects of PAO on tyrosine phosphorylation and granulocyte apoptosis. These results suggest that programmed eosinophil and neutrophil death is regulated by early events of signal transduction pathways such as tyrosine phosphorylation.
Yousefi
S
S
Swiss Institute of Allergy and Asthma Research, Davos.
Green
D R
DR
Blaser
K
K
Simon
H U
HU
D017209:Apoptosis; D001152:Arsenicals / Q000494:pharmacology; D004804:Eosinophils / Q000166:cytology* / Q000378:metabolism; D019833:Genistein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D019000:Phosphotyrosine; D015398:Signal Transduction; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D001152:Arsenicals; D007529:Isoflavones; C029341:oxophenylarsine; D019000:Phosphotyrosine; D014443:Tyrosine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019833:Genistein; D010749:Phosphoprotein Phosphatases