Tumor Necrosis Factor alpha (TNFα) reduces intestinal ascorbic acid (AA) uptake

Abstract

Intestinal inflammation and systemic bacterial infection are associated with an increase in the level of proinflammatory cytokines like tumor necrosis factor alpha (TNFα) in the intestinal mucosa and blood. Though important for intestinal immunity, TNFα also exerts profound effects on intestinal absorptive and secretory functions through specific intracellular signaling pathways like NF‐κB. Studies have shown that high levels of TNFα are linked to the pathogenesis of diarrhea in inflammatory bowel disease (IBD) and that these patients have low levels of vitamin C. To date, however, there has been little known about the effect of TNFα on intestinal absorption of vitamin C. Ouraim in this study was to address this issue using in vitro (Caco‐2), in vivo(mice), and ex vivo (enteroids) models, together with an array of physiological and molecular biological techniques. TreatingCaco‐2 cells and mice with TNFα led to a significant inhibition of 14C‐AAuptake compared to untreated controls. This inhibition was associated with significant decreases in SVCT‐1 protein, mRNA and hnRNA levels in TNFα treated Caco‐2 cells, mouse jejunum, and enteroids compared to their appropriate controls. TNFα also caused a significant inhibition in the activity of the SLC23A1 promoter in Caco‐2 cells. Further, treating Caco‐2 cells with the NF‐κB inhibitor celastrol blocked the inhibitory effect caused by TNFα on AA uptake, SVCT‐1 protein and mRNA expression, as well as SLC23A1 promoter activity. Finally, treatment of Caco‐2 cells with TNFα lead to a significant inhibition in the expression of the hepatocyte nuclear factor‐1α (HNF1α), which is known to drive the transcription of SLC23A1 promoter. Together, these findings demonstrate that TNFα inhibits intestinal AA uptake and that this effect is exerted, at least in part, at the level of transcription of the SLC23A1 gene through NF‐κB signaling pathway.Support or Funding InformationSupported by NIH grants DK 107474, DK 58057, DK 56057 and a grant from the DVA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.