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

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.

Analysis of Eosinophil Turnover In Vivo Reveals Their Active Recruitment to and Prolonged Survival in the Peritoneal Cavity

“…The proapoptotic BH3-only Bcl-2 homologue Bid is highly expressed in human eosinophils and gets activated by withdrawal of IL-5 or at least partially by Fas-mediated signals (32). It was further demonstrated that inhibitor of apoptosis proteins cIAP-2 and survivin were up-regulated in eosinophils by IL-5, IL-3, and GM-CSF and inhibited caspase-3 activation via the mitochondrial pathway but not via the Fas pathway (33). Although IL-5 has been shown to prolong eosinophil survival ex vivo, clinical trials aimed at reducing eosinophil counts in allergic asthma patients by anti-IL-5 therapy were rather unsuccessful.…”

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

“…Prolonged tissue survival has also been suggested to contribute to the accumulation of human eosinophils in nasal polyps (24), atopic dermatitis (25), bronchial asthma (26), and patients with eosinophilia (27,28; for a recent review on regulation of eosinophil apoptosis, see Ref. 29).…”

IL-3 induces a Pim1-dependent antiapoptotic pathway in primary human basophils

“…[1][2][3][4][5][6] Modulation of neutrophil and eosinophil apoptosis mediated by these cytokines has been suggested to rely on the up-regulation of antiapoptotic proteins of the Bcl-2 family, such as Bcl-2, Bcl-X L , Mcl-1 and A1, [7][8][9] as well as IAP family proteins. [10][11][12] With regards to signaling pathways, Janus kinase (JAK)/signal transducer and activator of transcription 3 and 5 (Stat3/Stat5), phosphatidylinositol 3-kinase (PI3-kinase), as well as p38-mitogen-activated protein kinase (MAPK) have been implicated in the regulation of neutrophil and eosinophil apoptosis by GM-CSF, IL-5, and IL-3. [13][14][15][16][17][18][19] Although previous studies showed that IL-3 prolongs the life span of basophils, 5,6 there is a complete lack of knowledge about the proteins and the mechanisms that regulate spontaneous and cytokineenhanced survival of basophils.…”