Wang Gangduo, Wang Jianling, Ma Huaxian, Khan M Firoze
Department of Pathology, University of Texas Medical Branch, 2.319 Mary Moody Northen, Galveston, TX 77555-0438, USA.
Toxicol Appl Pharmacol. 2009 Jun 1;237(2):188-95. doi: 10.1016/j.taap.2009.03.010. Epub 2009 Mar 28.
Even though reactive oxygen and nitrogen species (RONS) are implicated as mediators of autoimmune diseases (ADs), little is known about contribution of protein oxidation (carbonylation and nitration) in the pathogenesis of such diseases. The focus of this study was, therefore, to establish a link between protein oxidation and induction and/or exacerbation of autoimmunity. To achieve this, female MRL +/+ mice were treated with trichloroethene (TCE), an environmental contaminant known to induce autoimmune response, for 6 or 12 weeks (10 mmol/kg, i.p., every 4(th) day). TCE treatment resulted in significantly increased formation of nitrotyrosine (NT) and induction of iNOS in the serum at both 6 and 12 weeks of treatment, but the response was greater at 12 weeks. Likewise, TCE treatment led to greater NT formation, and iNOS protein and mRNA expression in the livers and kidneys. Moreover, TCE treatment also caused significant increases ( approximately 3 fold) in serum protein carbonyls (a marker of protein oxidation) at both 6 and 12 weeks. Significantly increased protein carbonyls were also observed in the livers and kidneys (2.1 and 1.3 fold, respectively) at 6 weeks, and to a greater extent at 12 weeks (3.5 and 2.1 fold, respectively) following TCE treatment. The increases in TCE-induced protein oxidation (carbonylation and nitration) were associated with significant increases in Th1 specific cytokine (IL-2, IFN-gamma) release into splenocyte cultures. These results suggest an association between protein oxidation and induction/exacerbation of autoimmune response. The results present a potential mechanism by which oxidatively modified proteins could contribute to TCE-induced autoimmune response and necessitates further investigations for clearly establishing the role of protein oxidation in the pathogenesis of ADs.
尽管活性氧和氮物种（RONS）被认为是自身免疫性疾病（ADs）的介质，但关于蛋白质氧化（羰基化和硝化）在这类疾病发病机制中的作用却知之甚少。因此，本研究的重点是建立蛋白质氧化与自身免疫诱导和/或加重之间的联系。为实现这一目标，对雌性MRL +/+小鼠用三氯乙烯（TCE）进行处理，TCE是一种已知可诱导自身免疫反应的环境污染物，处理6周或12周（10 mmol/kg，腹腔注射，每4天一次）。TCE处理在处理6周和12周时均导致血清中硝基酪氨酸（NT）形成显著增加和诱导型一氧化氮合酶（iNOS）产生，但在12周时反应更强。同样，TCE处理导致肝脏和肾脏中NT形成增加，以及iNOS蛋白和mRNA表达增加。此外，TCE处理在6周和12周时还导致血清蛋白羰基（蛋白质氧化的标志物）显著增加（约3倍）。TCE处理6周后，在肝脏和肾脏中也观察到蛋白羰基显著增加（分别为2.倍和1.3倍），在12周时增加程度更大（分别为3.5倍和2.1倍）。TCE诱导的蛋白质氧化（羰基化和硝化）增加与Th1特异性细胞因子（IL-2、IFN-γ）释放到脾细胞培养物中显著增加有关。这些结果表明蛋白质氧化与自身免疫反应的诱导/加重之间存在关联。这些结果提出了一种潜在机制，通过该机制氧化修饰的蛋白质可能促成TCE诱导的自身免疫反应，并且有必要进一步研究以明确确定蛋白质氧化在ADs发病机制中的作用。
