Lithocholic acid down-regulation of NF-κB activity through vitamin D receptor in colonic cancer cells

Abstract

Lithocholic acid (LCA), a secondary bile acid, is a vitamin D receptor (VDR) ligand. 1,25-Dihydroxyvitamin D 3 (1,25(OH) 2D 3), the hormonal form of vitamin D, is involved in the anti-inflammatory action through VDR. Therefore, we hypothesize that LCA acts like 1,25(OH) 2D 3 to drive anti-inflammatory signals. In present study, we used human colonic cancer cells to assess the role of LCA in regulation of the pro-inflammatory NF-κB pathway. We found that LCA treatment increased VDR levels, mimicking the effect of 1,25(OH) 2D 3. LCA pretreatment inhibited the IL-1β-induced IκBα degradation and decreased the NF-κB p65 phosphorylation. We also measured the production of IL-8, a well-known NF-κB target gene, as a read-out of the biological effect of LCA expression on NF-κB pathway. LCA significantly decreased IL-8 secretion induced by IL-1β. These LCA-induced effects were very similar to those of 1,25(OH) 2D 3. Thus, LCA recapitulated the effects of 1,25(OH) 2D 3 on IL-1β stimulated cells. Mouse embryonic fibroblast (MEF) cells lacking VDR have intrinsically high NF-κB activity. LCA pretreatment was not able to prevent TNFα-induced IκBα degradation in MEF VDR (−/−), whereas LCA stabilized IκBα in MEF VDR (+/−) cells. Collectively, our data indicated that LCA activated the VDR to block inflammatory signals in colon cells.