TNF-alpha induces transient resistance to Fas-induced apoptosis in eosinophilic acute myeloid leukemia cells.
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.
Qin
Yimin
Y
Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. yqin@medicine.bsd.uchicago.edu
Auh
Sogyong
S
Blokh
Lyubov
L
Long
Catherine
C
Gagnon
Isabelle
I
Hamann
Kimm J
KJ
D000208:Acute Disease; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D024202:Electrophoretic Mobility Shift Assay; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007951:Leukemia, Myeloid; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; C416282:BAY 11-7085; D053222:Fas Ligand Protein; D016328:NF-kappa B; D009570:Nitriles; D012717:Sesquiterpenes; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C002669:parthenolide; D051550:I-kappa B Kinase