Celada Lindsay J, Whalen Margaret M
Department of Biological Sciences, Tennessee State University, Nashville, TN, USA.
J Appl Toxicol. 2014 Sep;34(9):1002-11. doi: 10.1002/jat.2921. Epub 2013 Sep 5.
Butyltins (BTs) contaminate the environment and are found in human blood. BTs, tributyltin (TBT) and dibutyltin (DBT) diminish the cytotoxic function and levels of key proteins of human natural killer (NK) cells. NK cells are an initial immune defense against tumors, virally infected cells and antibody-coated cells and thus critical to human health. The signaling pathways that regulate NK cell functions include mitogen-activated protein kinases (MAPKs). Studies have shown that exposure to BTs leads to activation of specific MAPKs and MAPK kinases (MAP2Ks) in human NK cells. MAP2K kinases (MAP3Ks) are upstream activators of MAP2Ks, which then activate MAPKs. The current study examined if BT-induced activation of MAP3Ks was responsible for MAP2K and thus, MAPK activation. This study examines the effects of TBT and DBT on the total levels of two MAP3Ks, c-Raf and ASK1, as well as activating and inhibitory phosphorylation sites on these MAP3Ks. In addition, the immediate upstream activator of c-Raf, Ras, was examined for BT-induced alterations. Our results show significant activation of the MAP3K, c-Raf, in human NK cells within 10 min of TBT exposure and the MAP3K, ASK1, after 1 h exposures to TBT. In addition, our results suggest that both TBT and DBT affect the regulation of c-Raf.
丁基锡（BTs）污染环境并存在于人体血液中。BTs，即三丁基锡（TBT）和二丁基锡（DBT），会降低人类自然杀伤（NK）细胞的细胞毒性功能和关键蛋白水平。NK细胞是针对肿瘤、病毒感染细胞和抗体包被细胞的初始免疫防御，因此对人类健康至关重要。调节NK细胞功能的信号通路包括丝裂原活化蛋白激酶（MAPKs）。研究表明，接触BTs会导致人类NK细胞中特定的MAPKs和丝裂原活化蛋白激酶激酶（MAP2Ks）激活。MAP2K激酶（MAP3Ks）是MAP2Ks的上游激活剂，进而激活MAPKs。本研究探讨了BT诱导的MAP3Ks激活是否导致MAP2K以及因此导致的MAPK激活。本研究考察了TBT和DBT对两种MAP3Ks，即c-Raf和ASK1的总水平，以及这些MAP3Ks上的激活和抑制磷酸化位点的影响。此外，还研究了c-Raf的直接上游激活剂Ras在BT诱导下的变化。我们的结果显示，TBT暴露10分钟内，人类NK细胞中的MAP3K，即c-Raf显著激活，而TBT暴露1小时后，MAP3K，即ASK1激活。此外，我们的结果表明，TBT和DBT均影响c-Raf的调节。
