Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 38, Issue 1, Pages 121-124Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2007-0154OC
Keywords
eosinophils; apoptosis; caspases; mitochondria; Siglec-8
Funding
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI041472, R01AI072265, R21AI041472] Funding Source: NIH RePORTER
- NIAID NIH HHS [AI41472, R01 AI072265] Funding Source: Medline
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Previously, we have identified the sequential activation of reactive oxygen species (ROS), mitochondria, and caspase-3, -8, and -9, in Siglec-8-mediated, eosinophil apoptosis. Cytokine priming, which normally prolongs eosinophil survival, paradoxically potentiated this proapoptotic effect. The mechanisms of Siglec-8-mediated apoptosis after priming were therefore explored. Using IL-5 as the priming stimulus, the rate of Siglec-8-induced eosinophil apoptosis was found to be enhanced compared with unprimed cells, and mechanisms differed after IL-5 priming in that neither a pan-caspase inhibitor, nor a specific caspase-3 inhibitor, could override apoptosis. IL-5 priming also accelerated Siglec-8-mediated dissipation of mitochondrial membrane potential. Finally, both the mitochondrial electron transport inhibitor rotenone, and the RIDS inhibitors diphenyleneiodonium and antimycin, completely inhibited Siglec-8-mediated apoptosis, even after IL-5 priming. These data demonstrate that IL-5 priming enhances Siglec-8-mediated mitochondrial and ROS-dependent eosinophil apoptosis and eliminates caspase dependence. The potential clinical implication of these findings is that cytokine priming, as often occurs in vivo in asthma and other hyper-eosinophilic disorders, may render eosinophils from such patients especially susceptible to the proapoptotic effects of a Siglec-8-engaging therapeutic agent.
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