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http://purl.uniprot.org/citations/23684072http://www.w3.org/2000/01/rdf-schema#comment"

Background

Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is expressed on human eosinophils, where its ligation induces cell death. Paradoxically, Siglec-8-mediated cell death is markedly enhanced by the presence of the activation and survival factor IL-5 and becomes independent of caspase activity.

Objective

In this report we investigate the mechanism of Siglec-8-mediated cell death in activated eosinophils.

Methods

Human peripheral blood eosinophils were treated with agonistic anti-Siglec-8 antibody and IL-5, and cell death was determined by using flow cytometry and morphology. Phosphorylation of mitogen-activated protein kinase (MAPK) was determined by using phosphoLuminex, flow cytometry, and Western blotting. Reactive oxygen species (ROS) accumulation was determined by using dihydrorhodamine fluorescence.

Results

Costimulation with anti-Siglec-8 and IL-5 significantly increased the rate and proportion of cell death by means of necrosis accompanied by granule release compared with that seen after stimulation with anti-Siglec-8 alone, in which apoptosis predominated. Together with the caspase-independent mode of cell death in costimulated cells, these findings suggest the activation of a specific and distinct biochemical pathway of cell death during anti-Siglec-8/IL-5 costimulation. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and MAPK-ERK kinase (MEK) 1 was significantly enhanced and sustained in costimulated cells compared with that seen in cells stimulated with IL-5 alone; anti-Siglec-8 alone did not cause ERK1/2 phosphorylation. MEK1 inhibitors blocked anti-Siglec-8/IL-5-induced cell death. ROS accumulation was induced by Siglec-8 ligation in a MEK-independent manner. In contrast, an ROS inhibitor prevented the anti-Siglec-8/IL-5-induced enhancement of ERK phosphorylation and cell death. Exogenous ROS mimicked stimulation by anti-Siglec-8 and was sufficient to induce enhanced cell death in IL-5-treated cells. Collectively, these data suggest that the enhancement of ERK phosphorylation is downstream of ROS generation.

Conclusions

In activated eosinophils ligation of Siglec-8 leads to ROS-dependent enhancement of IL-5-induced ERK phosphorylation, which results in a novel mode of biochemically regulated eosinophil cell death."xsd:string
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http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/author"Zimmermann N."xsd:string
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/author"Bochner B.S."xsd:string
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/author"Kano G."xsd:string
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/author"Almanan M."xsd:string
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/date"2013"xsd:gYear
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/name"J Allergy Clin Immunol"xsd:string
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/pages"437-445"xsd:string
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/title"Mechanism of Siglec-8-mediated cell death in IL-5-activated eosinophils: role for reactive oxygen species-enhanced MEK/ERK activation."xsd:string
http://purl.uniprot.org/citations/23684072http://purl.uniprot.org/core/volume"132"xsd:string
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