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Fas Resistance of Leukemic Eosinophils Is Due to Activation of NF-B by Fas Ligation¹

Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637

TNF family receptors can lead to the activation of NF-B and this can be a prosurvival signal in some cells. Although activation of NF-B by ligation of Fas (CD95/Apo-1), a member of the TNFR family, has been observed in a few studies, Fas-mediated NF-B activation has not previously been shown to protect cells from apoptosis. We examined the Fas-induced NF-B activation and its antiapoptotic effects in a leukemic eosinophil cell line, AML14.3D10, an AML14 subline resistant to Fas-mediated apoptosis. EMSA and supershift assays showed that agonist anti-Fas (CH11) induced nuclear translocation of NF-B heterodimer p65(RelA)/p50 in these cells in both a time- and dose-dependent fashion. The influence of NF-B on the induction of apoptosis was studied using pharmacological proteasome inhibitors and an inhibitor of IB phosphorylation to block IB dissociation and degradation. These inhibitors at least partially inhibited NF-B activation and augmented CH11-induced cell death. Stable transfection and overexpression of IB in 3D10 cells inhibited CH11-induced NF-B activation and completely abrogated Fas resistance. Increases in caspase-8 and caspase-3 cleavage induced by CH11 and in consequent apoptotic killing were observed in these cells. Furthermore, while Fas-stimulation of resistant control 3D10 cells led to increases in the antiapoptotic proteins cellular inhibitor of apoptosis protein-1 and X-linked inhibitor of apoptosis protein, Fas-induced apoptosis in IB-overexpressing cells led to the down-modulation of both of these proteins, as well as that of the Bcl-2 family protein, Bcl-x_L. These data suggest that the resistance of these leukemic eosinophils to Fas-mediated killing is due to induced NF-B activation.

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