Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sialic acid binding immunoglobulin like lectin (Siglec)-8 crosslinking with specific antibodies causes human eosinophil apoptosis. Mechanisms by which Siglec-8 crosslinking induces apoptosis are not known. Peripheral blood eosinophils were examined for caspase, mitochondria and reactive oxygen species (ROS) involvement after incubating the cells with anti-Siglec-8 crosslinking Abs or control Abs, in the presence or absence of selective inhibitors. Siglec-8 crosslinking induced rapid cleavage of caspase-3, caspase-8, and caspase-9 in eosinophils. Selective caspase-8 and/or caspase-9 inhibitors inhibited this apoptosis. Siglec-8 crosslinking on eosinophils increased dissipation of mitochondrial membrane potential upstream of caspase activation. Rotenone and antimycin, inhibitors of mitochondrial respiratory chain components, completely inhibited apoptosis. Additional experiments with an inhibitor of ROS, diphenyleneiodonium, demonstrated that ROS was also essential for Siglec-8-mediated apoptosis and preceded Siglec-8-mediated mitochondrial dissipation. These experiments show that Siglec-8-induced apoptosis occurs through the sequential production of ROS, followed by induction of mitochondrial injury and caspase cleavage.
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PMID:Mechanism of Siglec-8-induced human eosinophil apoptosis: role of caspases and mitochondrial injury. 1615 3

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.
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PMID:Interleukin-5 priming of human eosinophils alters siglec-8 mediated apoptosis pathways. 1769 Mar 26