Tumor necrosis factor alpha (TNF-α) reduces intestinal vitamin C uptake. - GreenMedInfo Summary

Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal vitamin C uptake. Intestinal inflammation and prolonged infection are associated with an increased serum and intestinal mucosa levels of TNF-α, which also exerts profound effects on intestinal absorption process. Elevated levels of TNF-α have been linked to the pathogenesis of IBD and malabsorption of nutrients and these patients have low levels of vitamin C. To date, little is known about the effect of TNF-α on intestinal absorptionof vitamin C. We studied the impact of TNF-α on ascorbic acid (AA) transport using variety of intestinal preparations. The expression level of hSVCT-1 mRNA is significantly lower in IBD patients. TNF-α treated Caco-2 cells and mice showed a significant inhibition of intestinalC-AA uptake. This inhibition was associated with significant decreases in SVCT-1 protein, mRNA and hnRNA levels in TNF-α treated Caco-2 cells, mouse jejunum, and enteroids. Also, TNF-α caused a significant inhibition in the SLC23A1 promoter activity. Furthermore, treatment of Caco-2 cells with celastrol (NF-κB inhibitor) blocked the inhibitory effect caused by TNF-α on AA uptake, SVCT-1 protein and mRNA expression, as well as the activity of SLC23A1 promoter. Treatment of TNF-α also led to a significant decrease in the expression of HNF1α, which drives the basal activity of SLC23A1 promoter and this effect was reversed by celastrol. Together, these findings show that TNF-α inhibits intestinal AA uptakeand this effect is mediated, at least in part, at the level of transcription of the SLC23A1 gene via the NF-κB pathway.