Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis.
Sialic acid binding immunoglobulin-like lectin 8 (Siglec-8), which exists in 2 isoforms including one possessing cytoplasmic tyrosine motifs, is expressed only on human eosinophils, basophils, and mast cells. Until now, its function was unknown. Here we define a novel function of Siglec-8 on eosinophils. Siglec-8 cross-linking with antibodies rapidly generated caspase-3-like activity and reduced eosinophil viability through induction of apoptosis. The pancaspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp-(Ome)-fluoromethyl ketone (zVAD-FMK) completely blocked this response, implicating caspases in Siglec-8 cross-linking-induced apoptosis. Eosinophil survival-promoting cytokines such as interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) failed to block apoptosis and instead enhanced the sensitivity of eosinophils to undergo apoptosis in response to Siglec-8 antibody. Siglec-8 activation may provide a useful therapeutic approach to reduce numbers of eosinophils (and perhaps basophils and mast cells) in disease states where these cells are important.
Nutku
Esra
E
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Aizawa
Hideyuki
H
Hudson
Sherry A
SA
Bochner
Bruce S
BS
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000737:chemistry / Q000166:cytology* / Q000276:immunology; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D015848:Interleukin-5 / Q000494:pharmacology; D037102:Lectins / Q000032:analysis / Q000378:metabolism*; D017452:Receptors, IgG / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D061945:Caspase Inhibitors; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D007140:Immunoglobulin Fab Fragments; D015848:Interleukin-5; D037102:Lectins; D017452:Receptors, IgG; C403967:SIGLEC8 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases