Lefkowitz Doris L, Lefkowitz Stanley S
School of Biological Sciences, Section of Molecular Genetics and Microbiology, University of Texas at Austin, 1 University Station A5000, Austin, TX 78712-0162, USA.
Free Radic Biol Med. 2008 Sep 1;45(5):726-31. doi: 10.1016/j.freeradbiomed.2008.05.021. Epub 2008 Jun 3.
The role of inflammation in Alzheimer's disease, Parkinson's disease, and multiple sclerosis has recently come under increased scrutiny. Associated with these inflammatory responses are tumor necrosis factor-alpha (TNF-alpha) and reactive oxygen species (ROS), both believed to be derived from brain microglia. In addition to the above, the presence of myeloperoxidase (MPO) in these diseased brains has been reported by a number of investigators. However, the possible role of MPO and enzymatically inactive MPO (iMPO) as the "choreographers" of the destruction done by TNF-alpha and ROS is not generally recognized. Previously, our laboratory has reported that MPO/iMPO enhance macrophage generation of ROS and expression of proinflammatory cytokine genes as well as gene products. Recent studies in our laboratory indicate that the same response occurs with microglia. A paradigm is presented for the perpetuation of inflammation associated with neurodegenerative diseases. This model describes the unrecognized consequences of the stimulation of microglia by MPO or iMPO. Both MPO and iMPO and/or its receptor may represent new therapeutic targets for the treatment of these diseases.
炎症在阿尔茨海默病、帕金森病和多发性硬化症中的作用最近受到了越来越多的审视。与这些炎症反应相关的是肿瘤坏死因子-α（TNF-α）和活性氧（ROS），两者都被认为源自脑小胶质细胞。除上述情况外，许多研究人员报告了这些患病大脑中髓过氧化物酶（MPO）的存在。然而，MPO和无酶活性的MPO（iMPO）作为TNF-α和ROS造成破坏的“编排者”的潜在作用尚未得到普遍认可。此前，我们实验室报告称，MPO/iMPO可增强巨噬细胞ROS的生成、促炎细胞因子基因及其基因产物的表达。我们实验室最近的研究表明，小胶质细胞也会出现同样的反应。本文提出了一种与神经退行性疾病相关的炎症持续存在的范例。该模型描述了MPO或iMPO刺激小胶质细胞产生的未被认识到的后果。MPO和iMPO及/或其受体可能代表了治疗这些疾病的新治疗靶点。
