TL1A-induced NF-κB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells
TL1A-induced NF-κB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells
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DOI：
10.1074/jbc.m305833200
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发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Wei, P
中科院分区：
文献类型：
--
作者：
Wen, L;Zhuang, L;Wei, P
我们最近发现了TL1A，一种内皮来源的T细胞共刺激因子，也是肿瘤坏死因子受体超家族成员DR3和诱骗受体3(1)的配体。为了阐明TL1A和DR3相互作用所触发的信号转导事件，并了解DR3介导的细胞凋亡的分子机制，我们研究了TL1A和激动型DR3单抗对内源性表达DR3的人红白血病TF-1细胞的作用。TL1a可诱导含有Tradd、TRAF2和RIP的DR3信号复合体的形成，并激活核因子-kappaB、ERK、JNK和p38丝裂原活化蛋白激酶通路。然而，TL1a或激动型DR3单抗不能诱导这些细胞的凋亡，在信号复合体中也没有检测到FADD或原caspase-8的水平。有趣的是，在存在核因子-kappaB途径特异性抑制剂的情况下，DR3介导的细胞凋亡在TF-1细胞中被诱导，而在丝裂原激活的蛋白激酶抑制剂单独或联合存在的情况下则不被诱导，这表明DR3诱导的核因子-kappaB的激活是这些细胞抵抗凋亡的原因。与此一致，我们发现TL1A显著增加了c-IAP2的产生，c-IAP2是一种已知的依赖于NF-kappaB的抗凋亡蛋白，而NF-kappaB抑制剂或放线菌亚胺阻止了它的合成。此外，通过RNA干扰抑制c-IAP2的产生显著增强了TF-1细胞对TL1A诱导的细胞凋亡的敏感性。我们的研究确定了TL1A和DR3在TF-1细胞中调节细胞命运的分子机制。
We recently identified TL1A, an endothelium-derived T cell costimulator and a ligand for tumor necrosis factor receptor superfamily members DR3 and decoy receptor 3 (1). To elucidate the signaling events triggered by TL1A-DR3 interaction and to understand the molecular mechanisms regulating DR3-mediated apoptosis, we have studied the effect of TL1A and an agonistic DR3 monoclonal antibody in human erythroleukemic TF-1 cells, which express DR3 endogenously. TL1A induced the formation of a DR3 signaling complex containing TRADD, TRAF2, and RIP and activated the NF-kappaB and the ERK, JNK, and p38 mitogen-activated protein kinase pathways. However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or pro-caspase-8 seen in the signaling complex. Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-kappaB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-kappaB activation was responsible for resistance to apoptosis in these cells. Consistent with this, we found that TL1A significantly increased the production of c-IAP2, a known NF-kappaB-dependent anti-apoptotic protein, and that the NF-kappaB inhibitor or cycloheximide prevented its synthesis. Furthermore, inhibition of c-IAP2 production by RNA interference significantly sensitized TF-1 cells to TL1A-induced apoptosis. Our study identifies a molecular mechanism by which TL1A and DR3 regulate cell fate in TF-1 cells.