癌症患者自然杀伤细胞（NK）细胞毒性受损的一种可能机制：转化生长因子-β1（TGF-β1）导致DAP10下调。
A possible mechanism of impaired NK cytotoxicity in cancer patients: down-regulation of DAP10 by TGF-beta1.
作者信息
Lee June-Chul, Lee Kyung-Mi, Ahn Yong-Oon, Suh Beomseok, Heo Dae Seog
机构信息
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
出版信息
Tumori. 2011 May-Jun;97(3):350-7. doi: 10.1177/030089161109700316.
AIMS AND BACKGROUND
Elevated TGF-BETA1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. However, the molecular mechanism of immunosuppression by TGF-BETA1 is not yet clarified.
METHODS
IL-2-activated human NK cells were cultured with TGF-BETA1. Protein levels of NKG2D and DAP10 were examined by FACS or immunoblot analyses. Real-time RTPCR was performed to quantify the transcription levels. MAPK inhibitors were used to investigate intracellular signaling.
RESULTS
TGF-BETA1 down-regulated total and surface NKG2D, which was partially dependent on transcriptional regulation. TGF-BETA1 treatment of human NK cells resulted in significant changes in both transcriptional and translational levels of DAP10. Moreover, treatment with bafilomycin A1 or folimycin restored total NKG2D levels in TGF-BETA1-treated NK cells. The impaired NKG2D down-modulation by TGF-BETA1 was not associated with activation of the MAPK signaling pathway.
CONCLUSIONS
TGF-BETA1 down-modulates surface NKG2D expression by controlling the transcriptional and translational levels of DAP10.
目的与背景
转化生长因子β1（TGF-β1）分泌升高及自然杀伤细胞2D（NKG2D）下调是癌症患者自然杀伤（NK）细胞毒性受损的基础。然而，TGF-β1免疫抑制的分子机制尚未阐明。
方法
用TGF-β1培养白细胞介素-2激活的人NK细胞。通过荧光激活细胞分选术（FACS）或免疫印迹分析检测NKG2D和DNAX辅助蛋白10（DAP10）的蛋白质水平。进行实时逆转录聚合酶链反应（RT-PCR）以量化转录水平。使用丝裂原活化蛋白激酶（MAPK）抑制剂研究细胞内信号传导。
结果
TGF-β1下调总NKG2D和表面NKG2D，这部分依赖于转录调控。TGF-β1处理人NK细胞导致DAP10的转录和翻译水平均发生显著变化。此外，用巴弗洛霉素A1或佛利霉素处理可恢复TGF-β1处理的NK细胞中的总NKG2D水平。TGF-β1对NKG2D下调的损害与MAPK信号通路的激活无关。
结论
TGF-β1通过控制DAP10的转录和翻译水平下调表面NKG2D表达。
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