Reduction of CXC Chemokine Receptor 3 in an In Vitro Model of Continuous Exposure to Asbestos in a Human T-Cell Line, MT-2
Reduction of CXC Chemokine Receptor 3 in an In Vitro Model of Continuous Exposure to Asbestos in a Human T-Cell Line, MT-2
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DOI：
10.1165/rcmb.2010-0213oc
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发表时间：
2011-09-01
影响因子：
6.4
通讯作者：
Otsuki, Takemi
中科院分区：
文献类型：
--
作者：
Maeda, Megumi;Nishimura, Yasumitsu;Otsuki, Takemi
由于长期暴露于二氧化硅颗粒的矽肺患者不仅会发生肺纤维化，而且还会发生涉及自身免疫性疾病（如类风湿性关节炎和系统性硬化症）的并发症，因此暴露于石棉可能会影响人体免疫系统。这种免疫效应可能会损害抗肿瘤免疫功能，因为在接触石棉的患者中发现了肺癌和恶性间皮瘤等癌症并发症。为探讨石棉暴露对CD 4（+）T细胞抗肿瘤免疫功能的影响，采用人成T细胞白血病病毒1型永生化的人多克隆T细胞系MT-2，建立了长期低剂量石棉暴露的体外T细胞模型，并观察到6个亚系在连续暴露8个月后对石棉诱导的细胞凋亡具有抵抗作用。DNA微阵列分析结果显示，长期低浓度石棉暴露改变了139个基因的表达，与未暴露于石棉的MT-2细胞相比，这6个亚系的基因表达谱几乎相似。通路和网络分析表明，下调IFN-γ信号转导和表达的CXC趋化因子受体3（CXCR 3）的亚系，而ELISA和流式细胞术分析表明，减少Th 1相关的IFN-γ的生产和细胞表面CXCR 3的表达。这些发现表明，长期接触石棉可能会降低CD 4（+）T细胞的抗肿瘤免疫状态，体外T细胞模型可能有助于识别与抗肿瘤免疫功能受损相关的分子。
Because patients with silicosis who are chronically exposed to silica particles develop not only pulmonary fibrosis, but also complications involving autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, exposure to asbestos may affect the human immune system. This immunologic effect may impair antitumor immune function because cancer complications such as lung cancer and malignant mesothelioma are found in patients exposed to asbestos. To elucidate the antitumor immune status caused by CD4(+) T cells exposed to asbestos, an in vitro T-cell model of long-term and low-level exposure to chrysotile asbestos was established from a human adult T-cell leukemia virus-1-immortalized human polyclonal T cell line, MT-2, and the resulting six sublines showed resistance to asbestos-induced apoptosis after more than 8 months of continuous exposure. The results of DNA microarray analysis showed that the expression of 139 genes was altered by long-term and low-level exposure to asbestos, and the profile was almost similar among the six sublines when compared with the original MT-2 cells that had never been exposed to asbestos. Pathway and network analysis indicated a down-regulation of IFN-gamma signaling and expression of CXC chemokine receptor 3 (CXCR3) in the sublines, whereas ELISA and flow cytometry analysis demonstrated a reduction in Th1-related IFN-gamma production and cell-surface CXCR3 expression. These findings suggest that chronic exposure to asbestos may reduce antitumor immune status in CD4(+) T cells, and that an in vitro T-cell model may be useful in identifying molecules related to the impairment of antitumor immune function.