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  • Title: TNF-alpha induces transient resistance to Fas-induced apoptosis in eosinophilic acute myeloid leukemia cells.
    Author: Qin Y, Auh S, Blokh L, Long C, Gagnon I, Hamann KJ.
    Journal: Cell Mol Immunol; 2007 Feb; 4(1):43-52. PubMed ID: 17349210.
    Abstract:
    Tumor necrosis factor alpha (TNF-alpha) has been recognized as an activator of nuclear factor kappaB (NF-kappaB), a factor implicated in the protection of many cell types from apoptosis. We and others have presented evidence to suggest that Fas-induced apoptosis may be an important aspect of the resolution of inflammation, and that delayed resolution of inflammation may be directly associated with NF-kappaB-dependent resistance to Fas. Because TNF-alpha activates NF-kappaB in many cell types including inflammatory cells such as eosinophils, we examined effects of TNF-alpha signaling on the Fas-mediated killing of an eosinophilic cell line AML14. While agonist anti-Fas (CH11) treatment induced apoptosis in AML14 cells, no significant cell death occurred in response to TNF-alpha alone. Electrophoretic mobility shift assay (EMSA) revealed that TNF-alpha induced NF-kappaB transactivation in AML14 cells in a time- and dose-dependent fashion, and subsequent supershift assays indicated that the translocated NF-kappaB was the heterodimer p65 (RelA)/p50. Pre-treatment of cells with TNF-alpha dramatically decreased the CH11-induced cell death in a transient fashion, accompanied by suppression of activation of caspase-8 and caspase-3 activation. Inhibition of NF-kappaB transactivation by inhibitors, BAY 11-7085 and parthenolide, reversed the suppression of Fas-mediated apoptosis by TNF-alpha. Furthermore, TNF-alpha up-regulated X-linked inhibitor of apoptosis protein (XIAP) transiently and XIAP levels were correlated with the temporal pattern of TNF-alpha protection against Fas-mediated apoptosis. This finding suggested that TNF-alpha may contribute to the prolonged survival of inflammatory cells by suppression of Fas-mediated apoptosis, the process involved with NF-kappaB transactivation, anti-apoptotic XIAP up-regulation and caspase suppression.
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