Send to

Choose Destination
Am J Physiol Cell Physiol. 2018 Nov 1;315(5):C653-C663. doi: 10.1152/ajpcell.00295.2018. Epub 2018 Aug 29.

Effect of the proinflammatory cytokine TNF-α on intestinal riboflavin uptake: inhibition mediated via transcriptional mechanism(s).

Anandam KY1,2,3, Alwan OA1,2,3, Subramanian VS1,2,3, Srinivasan P1,2,3, Kapadia R1,2,3, Said HM1,2,3.

Author information

Department of Medicine, University of California , Irvine, California.
Department of Physiology/Biophysics, University of California , Irvine, California.
Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California.


Riboflavin (RF), is essential for normal cellular metabolism/function. Intestinal RF absorption occurs via a specific carrier-mediated process that involves the apical transporter RFVT-3 ( SLC52A3) and the basolateral RFVT-1 (SLC52A1). Previously, we characterized different cellular/molecular aspects of the intestinal RF uptake process, but nothing is known about the effect of proinflammatory cytokines on the uptake event. We addressed this issue using in vitro, ex vivo, and in vivo models. First, we determined the level of mRNA expression of the human (h)RFVT-3 and hRFVT-1 in intestinal tissue of patients with inflammatory bowel disease (IBD) and observed a markedly lower level compared with controls. In the in vitro model, exposing Caco-2 cells to tumor necrosis factor-α (TNF-α) led to a significant inhibition in RF uptake, an effect that was abrogated upon knocking down TNF receptor 1 (TNFR1). The inhibition in RF uptake was associated with a significant reduction in the expression of hRFVT-3 and -1 protein and mRNA levels, as well as in the activity of the SLC52A3 and SLC52A1 promoters. The latter effects appear to involve Sp1 and NF-κB sites in these promoters. Similarly, exposure of mouse small intestinal enteroids and wild-type mice to TNF-α led to a significant inhibition in physiological and molecular parameters of intestinal RF uptake. Collectively, these findings demonstrate that exposure of intestinal epithelial cells to TNF-α leads to inhibition in RF uptake and that this effect is mediated, at least in part, via transcriptional mechanism(s). These findings may explain the significantly low RF levels observed in patients with IBD.


, ; TNF-α; intestinal transport, riboflavin


Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center