Kaur Kuljeet, Sharma Anita K, Dhingra Sanjiv, Singal Pawan K
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, Winnipeg, Manitoba, Canada, R2H 2A6.
J Mol Cell Cardiol. 2006 Dec;41(6):1023-30. doi: 10.1016/j.yjmcc.2006.08.005. Epub 2006 Oct 11.
Oxidative stress and inflammation are considered to be important factors in the pathogenesis of congestive heart failure subsequent to myocardial infarction. Endogenous TNF-alpha plays a central role in initiating and sustaining the inflammatory response. IL-10, an anti-inflammatory cytokine, has been shown to antagonize some of the deleterious effects of TNF-alpha. In this study, we tested whether an imbalance of these two contrasting cytokines leads to increased oxidative stress and cardiac myocyte dysfunction. Isolated adult rat cardiac myocytes were exposed to different concentrations of TNF-alpha and IL-10 (1-20 ng/ml) alone or in combination. As a positive control, cells were also exposed to H2O2 (100 microI) to induce oxidative stress. An exposure to TNF-alpha (10 ng/ml) caused a significant decrease in both protein and mRNA for manganese superoxide dismutase and catalase, decreased glutathione peroxidase protein, increased intracellular reactive oxygen species and lipid peroxidation, and caused cell injury as measured by creatine kinase release. IL-10 treatment (10 ng/ml) by itself had no effect on any of these parameters, but it prevented all the above listed changes caused by TNF-alpha. IL-10/TNF-alpha ratio of lower or higher than 1 was less effective in reducing TNF-alpha generated oxidative stress. H2O2 treatment increased oxidative stress and cell injury and TNF-alpha mimicked these effects. This study suggests that a proper balance between IL-10 and TNF-alpha, rather than any of the individual cytokines is of more physiological importance in mediating oxidative-stress-induced cardiac injury.
氧化应激和炎症被认为是心肌梗死后充血性心力衰竭发病机制中的重要因素。内源性肿瘤坏死因子-α（TNF-α）在启动和维持炎症反应中起核心作用。白细胞介素-10（IL-10）是一种抗炎细胞因子，已被证明可拮抗TNF-α的一些有害作用。在本研究中，我们测试了这两种相反细胞因子的失衡是否会导致氧化应激增加和心肌细胞功能障碍。将成年大鼠分离的心肌细胞单独或联合暴露于不同浓度的TNF-α和IL-10（1-20 ng/ml）。作为阳性对照，细胞也暴露于过氧化氢（H2O2，100 μl）以诱导氧化应激。暴露于TNF-α（10 ng/ml）导致锰超氧化物歧化酶和过氧化氢酶的蛋白质和mRNA显著减少，谷胱甘肽过氧化物酶蛋白减少，细胞内活性氧和脂质过氧化增加，并导致肌酸激酶释放所测量的细胞损伤。单独的IL-10处理（10 ng/ml）对这些参数中的任何一个都没有影响，但它阻止了TNF-α引起的所有上述变化。IL-10/TNF-α比值低于或高于1在减轻TNF-α产生的氧化应激方面效果较差。H2O2处理增加了氧化应激和细胞损伤，TNF-α模拟了这些作用。这项研究表明，在介导氧化应激诱导的心脏损伤中，IL-10和TNF-α之间的适当平衡比任何一种单独的细胞因子在生理上更重要。
