Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and TNFα have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNFα on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNFα on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNFα inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNFα also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNFα decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-κB inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF-κB factors.

中文翻译：

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脂多糖和TNFα对神经元抗坏血酸摄取的影响

维生素 C（抗坏血酸：AA）在神经元中的摄取通过钠依赖性维生素 C 转运蛋白 2 (SVCT2) 发生，该转运蛋白在中枢神经系统 (CNS) 中高度表达。在慢性神经炎症或感染期间，CNS 的脂多糖 (LPS) 和 LPS 诱导的肿瘤坏死因子-α (TNFα )水平升高。LPS 和 TNF α水平升高与神经退行性疾病以及 AA 水平降低有关。然而，关于 LPS 和 TNF α对神经元 AA 摄取的影响知之甚少。本研究的目的是在体外和体内检查 LPS 和 TNF α对 SVCT2 表达和功能的影响方法。用 LPS 或 TNF α处理 SH-SY5Y 细胞可抑制 AA 摄取。这种减少的摄取与 SVCT2 蛋白和 mRNA 水平的显着降低有关。体内暴露于 LPS 或 TNF α也降低了小鼠大脑中的 SVCT2 蛋白和 mRNA 水平。LPS 和 TNF α都降低了 SLC23A2启动子的活性。此外，当转录因子 Sp1 的结合位点发生突变或用 NF- κ B 抑制剂 celastrol处理细胞时，LPS 对最小SLC23A2启动子的抑制作用减弱。我们得出结论，炎症信号通过损害SLC23A2来抑制 AA 的摄取通过对 Sp1 和 NF-κB 因子的反向调节进行转录。