Caspases mediate tumor necrosis factor-alpha-induced neutrophil apoptosis and downregulation of reactive oxygen production

Citation
K. Yamashita et al., Caspases mediate tumor necrosis factor-alpha-induced neutrophil apoptosis and downregulation of reactive oxygen production, BLOOD, 93(2), 1999, pp. 674-685
Citations number
81
Categorie Soggetti
Hematology,"Cardiovascular & Hematology Research
Journal title
BLOOD
ISSN journal
00064971 → ACNP
Volume
93
Issue
2
Year of publication
1999
Pages
674 - 685
Database
ISI
SICI code
0006-4971(19990115)93:2<674:CMTNFN>2.0.ZU;2-5
Abstract
Tumor necrosis factor-alpha (TNF-alpha) exerts two separate effects on neut rophils, stimulating effector functions while simultaneously inducing apopt osis. We examined here the involvement of caspases in neutrophil apoptosis and the effect of TNF-alpha-induced apoptosis on reactive oxygen production . Immunoblotting and affinity labeling showed activation of caspase-8, casp ase-3, and a caspase with a large subunit of 18 kD (T18) in TNF-alpha-treat ed neutrophils. Active caspase-6 and -7 were not detectable in this cell ty pe. Caspase-8 activated caspase-3 and T18 in neutrophil cytoplasmic extract s. zVAD-fmk blocked neutrophil apoptosis, in parallel with the inhibition o f caspase activation. TNF-alpha-induced caspase activation was accompanied by a decrease in the ability of neutrophils to release superoxide anion. Co nversely, TNF-alpha treatment in the presence of zVAD-fmk caused a prolonge d augmentation of superoxide release. Granulocyte-macrophage colony-stimula ting factor inhibited TNF-alpha-induced caspase activation and apoptosis, w hile reversing the diminution in superoxide release. These observations not only suggest that a caspase cascade mediates apoptotic events and downregu lates oxygen radical production in TNF-alpha-treated neutrophils, but also raise the possibility that suppression of caspase activation with enhanced proinflammatory actions of TNF-cr may underlie the pathogenesis of inflamma tory diseases, (C) 1999 by The American Society of Hematology.