Interleukin-5 priming of human eosinophils alters siglec-8 mediated apoptosis pathways.
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.
Nutku-Bilir
Esra
E
Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA.
Hudson
Sherry A
SA
Bochner
Bruce S
BS
D015703:Antigens, CD / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004579:Electron Transport / Q000187:drug effects; D004804:Eosinophils / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015848:Interleukin-5 / Q000378:metabolism* / Q000494:pharmacology; D037102:Lectins / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009861:Onium Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D014475:Uncoupling Agents / Q000494:pharmacology
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D061945:Caspase Inhibitors; C508599:IL5 protein, human; D015848:Interleukin-5; D037102:Lectins; D009861:Onium Compounds; D017382:Reactive Oxygen Species; C403967:SIGLEC8 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D014475:Uncoupling Agents; D012402:Rotenone; C032456:antimycin; D000968:Antimycin A; C007517:diphenyleneiodonium; D020169:Caspases
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