Effect of Lipopolysaccharide and TNFα 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-...
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| Format: | Article |
| Language: | English |
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Wiley
2021-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2021/4157132 |
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| author | Veedamali S. Subramanian Trevor Teafatiller Anshu Agrawal Masashi Kitazawa Jonathan S. Marchant |
| author_facet | Veedamali S. Subramanian Trevor Teafatiller Anshu Agrawal Masashi Kitazawa Jonathan S. Marchant |
| author_sort | Veedamali S. Subramanian |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cfc1df3c379c48fb8d30faae558c7ca9 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-cfc1df3c379c48fb8d30faae558c7ca92025-02-03T01:00:47ZengWileyMediators of Inflammation0962-93511466-18612021-01-01202110.1155/2021/41571324157132Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid UptakeVeedamali S. Subramanian0Trevor Teafatiller1Anshu Agrawal2Masashi Kitazawa3Jonathan S. Marchant4Department of Medicine, University of California, Irvine, CA 92697, USADepartment of Medicine, University of California, Irvine, CA 92697, USADepartment of Medicine, University of California, Irvine, CA 92697, USADepartment of Medicine, University of California, Irvine, CA 92697, USADepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USAVitamin 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.http://dx.doi.org/10.1155/2021/4157132 |
| spellingShingle | Veedamali S. Subramanian Trevor Teafatiller Anshu Agrawal Masashi Kitazawa Jonathan S. Marchant Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake Mediators of Inflammation |
| title | Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake |
| title_full | Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake |
| title_fullStr | Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake |
| title_full_unstemmed | Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake |
| title_short | Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake |
| title_sort | effect of lipopolysaccharide and tnfα on neuronal ascorbic acid uptake |
| url | http://dx.doi.org/10.1155/2021/4157132 |
| work_keys_str_mv | AT veedamalissubramanian effectoflipopolysaccharideandtnfaonneuronalascorbicaciduptake AT trevorteafatiller effectoflipopolysaccharideandtnfaonneuronalascorbicaciduptake AT anshuagrawal effectoflipopolysaccharideandtnfaonneuronalascorbicaciduptake AT masashikitazawa effectoflipopolysaccharideandtnfaonneuronalascorbicaciduptake AT jonathansmarchant effectoflipopolysaccharideandtnfaonneuronalascorbicaciduptake |