Dimayuga Filomena O, Wang Chunmei, Clark Jordan M, Dimayuga Edgardo R, Dimayuga Vanessa M, Bruce-Keller Annadora J
Mn 222 Chandler Medical Center, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, United States.
J Neuroimmunol. 2007 Jan;182(1-2):89-99. doi: 10.1016/j.jneuroim.2006.10.003. Epub 2006 Nov 13.
Activation of the oxidative burst is one of the earliest biochemical events in microglial activation, but it is not understood yet how free radicals participate in inflammatory signaling. To determine the role that specific reactive oxygen species play in microglial activation, the levels of SOD1 were manipulated in N9 murine microglia. Stable overexpression of SOD1 caused significant decreases in superoxide and nitric oxide production, with concurrent increases in hydrogen peroxide following LPS. However, LPS-induced activation of NFkappaB, and release of TNFalpha and IL-6 were significantly attenuated in SOD1 overexpressing cells, as was the ability of microglia to induce toxicity in cultured neurons. Conversely, acute inhibition of SOD1 with disulfiram was associated with increased nitric oxide and cytokine release, and increased neurotoxicity. Together, these data suggest that superoxide radicals in microglia play important roles in directing redox-sensitive inflammatory signaling and initiating neurotoxic inflammation.
氧化爆发的激活是小胶质细胞激活过程中最早出现的生化事件之一，但自由基如何参与炎症信号传导尚不清楚。为了确定特定活性氧在小胶质细胞激活中所起的作用，在N9小鼠小胶质细胞中对超氧化物歧化酶1（SOD1）的水平进行了调控。SOD1的稳定过表达导致超氧化物和一氧化氮生成显著减少，同时脂多糖（LPS）刺激后过氧化氢生成增加。然而，在SOD1过表达的细胞中，LPS诱导的核因子κB（NFκB）激活以及肿瘤坏死因子α（TNFα）和白细胞介素6（IL-6）的释放均显著减弱，小胶质细胞在培养神经元中诱导毒性的能力也减弱。相反，用双硫仑急性抑制SOD1会导致一氧化氮和细胞因子释放增加以及神经毒性增强。这些数据共同表明，小胶质细胞中的超氧自由基在指导氧化还原敏感的炎症信号传导和引发神经毒性炎症中起重要作用。
