TNF-alpha induces transient resistance to Fas-induced apoptosis in eosinophilic acute myeloid leukemia cells.
TNF-alpha induces transient resistance to Fas-induced apoptosis in eosinophilic acute myeloid leukemia cells.
复制标题
DOI：
--
复制
发表时间：
2007
影响因子：
24.1
通讯作者：
Yimin Qin;S. Auh;Lyubov Blokh;C. Long;Isabelle A. Gagnon;K. Hamann
中科院分区：
文献类型：
--
作者：
Yimin Qin;S. Auh;Lyubov Blokh;C. Long;Isabelle A. Gagnon;K. Hamann
肿瘤坏死因子α（TNF-α）已被认为是核因子κ B（NF-κ B）的激活剂，核因子κ B是一种涉及保护许多细胞类型免于凋亡的因子。我们和其他人已经提出证据表明Fas诱导的细胞凋亡可能是炎症消退的一个重要方面，并且炎症消退延迟可能与NF-κ B依赖性Fas抗性直接相关。由于TNF-α在许多细胞类型中激活NF-κ B，包括炎性细胞如嗜酸性粒细胞，我们研究了TNF-α信号传导对Fas介导的嗜酸性细胞系AML 14的杀伤作用。虽然激动剂抗Fas（CH 11）治疗诱导AML 14细胞凋亡，但单独TNF-α没有显著的细胞死亡。电泳迁移率变动分析（EMSA）显示TNF-α以时间和剂量依赖性方式诱导AML 14细胞中NF-κ B的反式激活，随后的超迁移分析表明易位的NF-κ B是异源二聚体p65（RelA）/p50。用TNF-α预处理细胞以瞬时方式显著降低了CH 11诱导的细胞死亡，伴随着对caspase-8和caspase-3活化的抑制。抑制剂BAY 11-7085和parthenocyte对NF-κ B反式激活的抑制逆转了TNF-α对Fas介导的凋亡的抑制。此外，TNF-α上调X连锁的凋亡抑制蛋白（XIAP）瞬时和XIAP水平与TNF-α对Fas介导的细胞凋亡的保护的时间模式相关。这一发现表明TNF-α可能通过抑制Fas介导的细胞凋亡而有助于延长炎性细胞的存活，该过程涉及NF-κ B反式激活、抗细胞凋亡XIAP上调和caspase抑制。
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.