cIAP‐2 and survivin contribute to cytokine‐mediated delayed eosinophil apoptosis

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Abstract
The exact molecular mechanisms leading to delayed apoptosis, a phenomenon frequently observed in eosinophil inflammatory responses, remain largely unknown. Here, we show that cultured eosinophils purified from blood of hypereosinophilic syndrome (HES) patients exhibit delayed spontaneous death and relative resistance towards ceramide‐ but not CD95‐mediated death. The subsequent investigation of members of the inhibitor of apoptosis (IAP) family revealed that HES but not normal eosinophils expressed high levels of cellular IAP‐2 (cIAP‐2) and survivin. The eosinophil hematopoietins IL‐3, IL‐5, and GM‐CSF increased the expression of cIAP‐2 and survivin in normal eosinophils in vitro. In the blood of HES patients, we observed increased concentrations of IL‐3 and/or IL‐5, suggesting that these cytokines are, at least partially, responsible for the elevated levels of cIAP‐2 and survivin in the eosinophils of these patients. Utilizing a cell‐free system in which caspase‐3 was activated in eosinophil cytosolic extracts by addition of cytochrome c and immunodepletion of cIAP‐2 or survivin resulted in accelerated caspase activation. These data suggest that some members of the IAP family including survivin are regulated by survival cytokines and inhibit the caspase cascade in HES eosinophils. The cytokine‐dependent mechanism of delayed eosinophil apoptosis described here may also apply to other eosinophilic diseases.