The involvement of TNF-α-related apoptosis-inducing ligand in the enhanced cytotoxicity of IFN-β-stimulated human dendritic cells to tumor cells
The involvement of TNF-α-related apoptosis-inducing ligand in the enhanced cytotoxicity of IFN-β-stimulated human dendritic cells to tumor cells
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DOI：
10.4049/jimmunol.166.9.5407
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发表时间：
2001-05-01
影响因子：
4.4
通讯作者：
Cao, XT
中科院分区：
文献类型：
--
作者：
Liu, SX;Yu, YZ;Cao, XT
tnf - α相关的凋亡诱导配体（TRAIL）具有优先诱导肿瘤细胞而非正常细胞凋亡的特点。树突状细胞（DCs）除了具有apc的作用外，现已被证明对某些肿瘤细胞具有细胞毒性或细胞抑制作用。在这里，我们报道了人CD34（+）干细胞衍生的dc （cd34dc）和人CD14（+）单核细胞衍生的dc （MoDCs）都表达TRAIL，并部分通过TRAIL对某些类型的肿瘤细胞表现出细胞毒性。从培养第8天开始，在cd34dc上出现了TRAIL的中度表达，在新分离的单核细胞上也可以看到TRAIL的表达。在DC成熟之前，TRAIL的表达水平保持不变。ifn - β刺激后，未成熟cd34dc或MoDCs上TRAIL的表达显著上调。此外，ifn - β可以显著增强cd34dc或MoDCs杀死trail敏感肿瘤细胞的能力，而LPS则没有这种作用。在ifn - β刺激的dc上，TRAIL的上调部分促成了dc的细胞毒性增加。用caspase-3抑制剂预处理trail敏感的肿瘤细胞可显著增加其对ifn - β刺激的dc细胞毒性的抗性。相反，NF-kappaB抑制剂可显著提高肿瘤细胞对非刺激或lps刺激dc杀伤的敏感性。我们的研究表明，ifn - β刺激的dc具有功能性细胞毒性。因此，体内可能存在dc介导的抗肿瘤免疫的先天机制，其中dc作为效应物部分通过TRAIL直接杀伤肿瘤细胞。随后，dc作为apc参与凋亡肿瘤Ags的摄取、加工和向交叉引物CD8(+) CTL细胞的呈递。
TNF-alpha -related apoptosis-inducing ligand (TRAIL) is characterized by its preferential induction of apoptosis of tumor cells but not normal cells. Dendritic cells (DCs), besides their role as APCs, now have been demonstrated to exert cytotoxicity or cytostasis on some tumor cells. Here, we report that both human CD34(+) stem cell-derived DCs (CD34DCs) and human CD14(+) monocyte-derived DCs (MoDCs) express TRAIL and exhibit cytotoxicity to some types of tumor cells partially through TRAIL. Moderate expression of TRAIL appeared on CD34DCs from the 8th day of culture and was also seen on freshly isolated monocytes. The level of TRAIL expression remained constant until DC maturation. TRAIL expression on immature CD34DCs or MoDCs was greatly up-regulated after IFN-beta stimulation. Moreover, IFN-beta could strikingly enhance the ability of CD34DCs or MoDCs to kill TRAIL-sensitive tumor cells, but LPS did not have such an effect. The up-regulation of TRAIL on IFN-beta -stimulated DCs partially contributed to the increased cytotoxicity of DCs. Pretreatment of TRAIL-sensitive tumor cells with caspase-3 inhibitor could significantly increase their resistance to the cytotoxicity of IFN-beta -stimulated DCs. In contrast, NF-kappaB inhibitor could significantly increase the sensitivity of tumor cells to the killing by nonstimulated or LPS-stimulated DCs. Our studies demonstrate that IFN-beta -stimulated DCs are functionally cytotoxic. Thus, an innate mechanism of DC-mediated antitumor immunity might exist in vivo in which DCs act as effectors to directly kill tumor cells partially via TRAIL. Subsequently, DCs act as APCs involved in the uptake, processing, and presentation of apoptotic tumor Ags to cross-prime CD8(+) CTL cells.