Effect of Lipopolysaccharide and TNF on Neuronal Ascorbic Acid Uptake.

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- (TNF) are increased. Elevated levels of LPS and TNF have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNF on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNF on SVCT2 expression and function using and approaches. Treatment of SH-SY5Y cells with either LPS or TNF inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. exposure to LPS or TNF also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNF decreased promoter activity. Further, the inhibitory effect of LPS on a minimal promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-B inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing transcription through opposing regulation of Sp1 and NF-B factors.