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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >AGEs-RAGE mediated up-regulation of connexin43 in activated human microglial CHME-5 cells
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AGEs-RAGE mediated up-regulation of connexin43 in activated human microglial CHME-5 cells

机译：AGEs-RAGE介导活化的人小胶质细胞CHME-5细胞中的connexin43上调

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摘要

Microglial activation is a significant contributor to the pathogenesis of many neurodegenerative diseases. Microglia respond to a range of stimuli including pathogenic protein deposits such as advanced glycation endproducts (AGEs). AGEs are prominent inflammatory stimuli that accumulate in the ageing brain. AGEs can activate microglia, leading to the production of excessive amounts of inflammatory cytokines and coupling via gap junction proteins especially connexin43 (Cx43). The literature on the expression of microglial Cx43 during inflammation is controversial. Many cellular effects of AGEs are thought to be mediated by the receptor RAGE. There is however, no evidence suggesting Cx43 is a downstream effector of AGEs-RAGE interaction in microglia. In addition, most of the AGEs-related studies have been undertaken using rodent microglia; the information on human microglia is sparse. Microglia of human and rodent origin respond differently to certain stimuli. The aims of this study were to investigate the AGEs-RAGE-mediated activation of human microglia and establish if Cx43 is one of the downstream effectors of AGEs-RAGE interaction in these cells. Human microglial CHME-5 cells were treated with different doses of AGEs for a selected time-period and microglial activation studied using specific markers. The protein expression of RAGE, Cx43 and TNF-α-receptors (RI and RII) was analysed in response to AGEs in the absence/presence of various doses of anti-RAGE Fabs. TNF-α levels in media were measured using ELISA. TNF-α-induced opening of gap junctional channels was assessed by dye uptake assays and the effect of neutralising TNFRII on Cx43 levels was also studied. CHME-5 cells showed an up-regulation of RAGE, TNF-α, TNFRs (especially TNFRII) and Cx43 upon AGEs treatment and a significant dose-dependent drop in the levels of TNF-α, TNFRII and Cx43 in the presence of anti-RAGE Fabs. TNF-α induced gap junctional/hemichannel opening whereas blocking TNFRII inhibited TNF-α-induced increase in Cx43 levels. Results suggested that TNF-α, TNFRII and Cx43 are downstream effectors of the AGEs-RAGE interaction in human microglial CHME-5 cells.
机译：小胶质细胞活化是许多神经退行性疾病的发病机理的重要贡献。小胶质细胞对多种刺激作出反应，包括病原性蛋白质沉积，例如晚期糖基化终产物（AGEs）。 AGEs是在衰老的大脑中累积的突出的炎症刺激。 AGEs可以激活小胶质细胞，导致产生过多的炎症细胞因子，并通过缝隙连接蛋白特别是连接蛋白43（Cx43）偶联。关于炎症期间小胶质细胞Cx43表达的文献存在争议。 AGE的许多细胞作用被认为是由受体RAGE介导的。但是，没有证据表明Cx43是小胶质细胞中AGEs-RAGE相互作用的下游效应子。另外，大多数与AGEs相关的研究都是使用啮齿动物小胶质细胞进行的。有关人类小胶质细胞的信息很少。人类和啮齿动物起源的小胶质细胞对某些刺激的反应不同。这项研究的目的是调查AGEs-RAGE介导的人类小胶质细胞活化，并确定Cx43是否是这些细胞中AGEs-RAGE相互作用的下游效应器之一。在选定的时间段内，用不同剂量的AGEs处理人小胶质细胞CHME-5细胞，并使用特异性标记物研究小胶质细胞的活化。在不存在/存在各种剂量的抗RAGE Fabs的情况下，分析AGE对RAGE，Cx43和TNF-α受体（RI和RII）的蛋白表达。使用ELISA测量培养基中的TNF-α水平。 TNF-α诱导的间隙连接通道的开放通过染料摄取测定法进行评估，并且还研究了中和TNFRII对Cx43水平的影响。 CHME-5细胞在AGEs处理后显示RAGE，TNF-α，TNFRs（特别是TNFRII）和Cx43的上调，并且在存在抗-E的情况下，TNF-α，TNFRII和Cx43的水平呈剂量依赖性下降愤怒的工厂。 TNF-α诱导间隙连接/半通道开放，而阻断TNFRII则抑制TNF-α诱导的Cx43水平升高。结果表明，TNF-α，TNFRII和Cx43是人小胶质细胞CHME-5细胞中AGEs-RAGE相互作用的下游效应子。

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