Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Toxicol Appl Pharmacol. 2013 Nov 15;273(1):189-95. doi: 10.1016/j.taap.2013.08.020. Epub 2013 Aug 28.
Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, is known to induce autoimmunity both in humans and animal models. However, mechanisms underlying TCE-mediated autoimmunity remain largely unknown. Previous studies from our laboratory in MRL+/+ mice suggest that oxidative stress may contribute to TCE-induced autoimmune response. The current study was undertaken to further assess the role of oxidative stress in TCE-induced autoimmunity by supplementing with an antioxidant N-acetylcysteine (NAC). Groups of female MRL+/+ mice were given TCE, NAC or TCE+NAC for 6 weeks (TCE, 10mmol/kg, i.p., every 4th day; NAC, 250mg/kg/day through drinking water). TCE exposure led to significant increases in serum levels of anti-nuclear, anti-dsDNA and anti-Sm antibodies. TCE exposure also led to significant induction of anti-malondiadelhyde (MDA)- and anti-hydroxynonenal (HNE)-protein adduct antibodies which were associated with increased ANA in the sera along with increased MDA-/HNE-protein adducts in the livers and kidneys, and increases in protein oxidation (carbonylation) in the sera, livers and kidneys, suggesting an overall increase in oxidative stress. Moreover, TCE exposure also resulted in increased release of IL-17 from splenocytes and increases in IL-17 mRNA expression. Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera. These results provide further support to a role of oxidative stress in TCE-induced autoimmune response. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for preventive and/or therapeutic strategies.
三氯乙烯（TCE）是一种普遍存在的环境污染物，已知其在人类和动物模型中均可引起自身免疫。然而，TCE 介导的自身免疫的机制在很大程度上仍然未知。我们实验室之前在 MRL+/+小鼠中的研究表明，氧化应激可能导致 TCE 诱导的自身免疫反应。本研究旨在通过补充抗氧化剂 N-乙酰半胱氨酸（NAC）进一步评估氧化应激在 TCE 诱导的自身免疫中的作用。将雌性 MRL+/+小鼠分为 TCE、NAC 或 TCE+NAC 组，每组给予 TCE、NAC 或 TCE+NAC 处理 6 周（TCE，10mmol/kg，腹腔注射，每 4 天 1 次；NAC，通过饮用水给予 250mg/kg/天）。TCE 暴露导致血清中抗核、抗 dsDNA 和抗 Sm 抗体水平显著升高。TCE 暴露还导致抗丙二醛（MDA）和抗 4-羟基壬烯醛（HNE）-蛋白加合物抗体的显著诱导，这与血清中的 ANA 增加以及肝脏和肾脏中 MDA-/HNE-蛋白加合物的增加有关，并且血清、肝脏和肾脏中的蛋白质氧化（羰基化）增加，表明总体氧化应激增加。此外，TCE 暴露还导致脾细胞中白细胞介素-17（IL-17）的释放增加，以及 IL-17 mRNA 表达增加。值得注意的是，NAC 补充不仅减弱了 TCE 诱导的氧化应激、IL-17 释放和 mRNA 表达，还减弱了自身免疫标志物，如血清中 ANA、抗 dsDNA 和抗 Sm 抗体水平降低。这些结果进一步支持氧化应激在 TCE 诱导的自身免疫反应中的作用。NAC 减弱了 TCE 诱导的自身免疫，为预防和/或治疗策略提供了一种方法。
