Thomas LeeShawn D, Shah Hemangini, Green Stephanie A, Bankhurst Arthur D, Whalen Margaret M
Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Toxicology. 2004 Aug 5;200(2-3):221-33. doi: 10.1016/j.tox.2004.04.002.
Natural Killer (NK) cells are a subset of lymphocytes that are capable of killing tumor cells, virally infected cells and antibody coated cells. Tributyltin (TBT) is a toxic chemical used for various industrial purposes such as: slime control in paper mills, disinfection of circulating industrial cooling waters, anti-fouling agents in shower curtains and the preservation of wood. TBT can be found in edible items such as dairy products and fish. This study investigates the mechanism by which TBT exposure decreases the immune function of human NK cells, in vitro. Cytotoxic function, the expression of the cytotoxic proteins (granzyme B and perforin), and cAMP response element binding protein (CREB) phosphorylation were examined. NK cells exposed to 300 nM TBT for 1 h showed no significant decrease in cytotoxic function, levels of granzyme B and perforin, or phosphorylation of CREB. However, mRNA levels for the cytotoxic proteins were significantly decreased. A 24 h exposure to 200 nM TBT caused significant decreases in cytotoxic function, levels of granzyme B and perforin, and levels of granzyme B and perforin mRNA. When NK cells were exposed to 300 nM TBT for 1h followed by a 24 h period in TBT-free media, again there were significant decreases in NK cell cytotoxic function, levels of granzyme B and perforin and their mRNA. A 1h exposure to 300 nM TBT followed by a 48 h period in TBT-free media showed similar changes in cytotoxic function and levels of granzyme B and perforin as seen after 24 h in TBT-free media. Additionally, both of these exposures showed significant decreases in phosphorylation of CREB. These results indicate that TBT exposures can disrupt the transcription of granzyme B and perforin and that this disruption cannot be entirely accounted for by a decrease in phosphorylated CREB (phosphoCREB) levels.
自然杀伤（NK）细胞是淋巴细胞的一个亚群，能够杀伤肿瘤细胞、病毒感染细胞和抗体包被细胞。三丁基锡（TBT）是一种有毒化学物质，用于各种工业用途，如：造纸厂的黏液控制、工业循环冷却水的消毒、浴帘中的防污剂以及木材防腐。TBT可在乳制品和鱼类等可食用物品中发现。本研究在体外研究了TBT暴露降低人NK细胞免疫功能的机制。检测了细胞毒性功能、细胞毒性蛋白（颗粒酶B和穿孔素）的表达以及环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化。暴露于300 nM TBT 1小时的NK细胞在细胞毒性功能、颗粒酶B和穿孔素水平或CREB磷酸化方面没有显著降低。然而，细胞毒性蛋白的mRNA水平显著降低。暴露于200 nM TBT 24小时导致细胞毒性功能、颗粒酶B和穿孔素水平以及颗粒酶B和穿孔素mRNA水平显著降低。当NK细胞暴露于300 nM TBT 1小时，然后在无TBT培养基中培养24小时，NK细胞的细胞毒性功能、颗粒酶B和穿孔素水平及其mRNA再次显著降低。暴露于300 nM TBT 1小时，然后在无TBT培养基中培养48小时，细胞毒性功能以及颗粒酶B和穿孔素水平的变化与在无TBT培养基中培养24小时后的变化相似。此外，这两种暴露均显示CREB磷酸化显著降低。这些结果表明，TBT暴露可破坏颗粒酶B和穿孔素的转录，且这种破坏不能完全由磷酸化CREB（磷酸化CREB）水平的降低来解释。
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