Lithocholic acid (LCA), a secondary bile acid, is a vitamin D receptor (VDR) ligand.
1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(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)(2)D(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-kappaB pathway. We found that LCA treatment increased VDR levels, mimicking the
effect of 1,25(OH)(2)D(3). LCA pretreatment inhibited the IL-1beta-induced IkappaBalpha
degradation and decreased the NF-kappaB p65 phosphorylation. We also measured the
production of IL-8, a well-known NF-kappaB target gene, as a read-out of the biological
effect of LCA expression on NF-kappaB pathway. LCA significantly decreased IL-8 secretion
induced by IL-1beta. These LCA-induced effects were very similar to those of 1,25(OH)(2)D(3.)
Thus, LCA recapitulated the effects of 1,25(OH)(2)D(3) on IL-1beta stimulated cells.
Mouse embryonic fibroblast (MEF) cells lacking VDR have intrinsically high NF-kappaB
activity. LCA pretreatment was not able to prevent TNFalpha-induced IkappaBalpha degradation
in MEF VDR (-/-), whereas LCA stabilized IkappaBalpha in MEF VDR (+/-) cells. Collectively,
our data indicated that LCA activated the VDR to block inflammatory signals in colon
cells.