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

Kouhei Yamashita, Atsushi Takahashi, Susumu Kobayashi, Hirokazu Hirata, Peter W. Mesner, Scott H. Kaufmann, Shin Yonehara, Kokichi Yamamoto, Takashi Uchiyama, Masataka Sasada

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Abstract

Tumor necrosis factor-α (TNF-α) exerts two separate effects on neutrophils, stimulating effector functions while simultaneously inducing apoptosis. We examined here the involvement of caspases in neutrophil apoptosis and the effect of TNF-α-induced apoptosis on reactive oxygen production. Immunoblotting and affinity labeling showed activation of caspase-8, caspase-3, and a caspase with a large subunit of 18 kD (T18) in TNF-α-treated neutrophils. Active caspase-6 and -7 were not detectable in this cell type. Caspase-8 activated caspase-3 and T18 in neutrophil cytoplasmic extracts. zVAD-fmk blocked neutrophil apoptosis, in parallel with the inhibition of caspase activation. TNF-α-induced caspase activation was accompanied by a decrease in the ability of neutrophils to release superoxide anion. Conversely, TNF-α treatment in the presence of zVAD-fmk caused a prolonged augmentation of superoxide release. Granulocyte-macrophage colony- stimulating factor inhibited TNF-α-induced caspase activation and apoptosis, while reversing the diminution in superoxide release. These observations not only suggest that a caspase cascade mediates apoptotic events and downregulates oxygen radical production in TNF-α-treated neutrophils, but also raise the possibility that suppression of caspase activation with enhanced proinflammatory actions of TNF-α may underlie the pathogenesis of inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)674-685
Number of pages12
JournalBlood
Volume93
Issue number2
StatePublished - Jan 15 1999

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Yamashita, K., Takahashi, A., Kobayashi, S., Hirata, H., Mesner, P. W., Kaufmann, S. H., Yonehara, S., Yamamoto, K., Uchiyama, T., & Sasada, M. (1999). Caspases mediate tumor necrosis factor-α-induced neutrophil apoptosis and downregulation of reactive oxygen production. Blood, 93(2), 674-685.