TY - JOUR
T1 - Interleukin-5 priming of human eosinophils alters Siglec-8-mediated apoptosis pathways
AU - Nutku-Bilir, Esra
AU - Hudson, Sherry A.
AU - Bochner, Bruce S.
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2008/1
Y1 - 2008/1
N2 - 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 ROS 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 hypereosinophilic disorders, may render eosinophils from such patients especially susceptible to the proapoptotic effects of a Siglec-8-engaging therapeutic agent.
AB - 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 ROS 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 hypereosinophilic disorders, may render eosinophils from such patients especially susceptible to the proapoptotic effects of a Siglec-8-engaging therapeutic agent.
KW - Apoptosis
KW - Caspases
KW - Eosinophils
KW - Mitochondria
KW - Siglec-8
UR - http://www.scopus.com/inward/record.url?scp=37549035463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37549035463&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2007-0154OC
DO - 10.1165/rcmb.2007-0154OC
M3 - Article
C2 - 17690326
AN - SCOPUS:37549035463
VL - 38
SP - 121
EP - 124
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 1
ER -