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

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 111; no. 1-2; p. 37
• Main Authors: Sun, Jun, Mustafi, Reba, Cerda, Sonia, Chumsangsri, Anusara, Xia, Yinglin Rick, Li, Yan Chun, Bissonnette, Marc
• Format: Journal Article
• Language: English
• Published: England 01.07.2008
• Subjects: Caco-2 Cells; Cell Line, Tumor; Clone Cells; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Down-Regulation - drug effects; HT29 Cells; Humans; Lithocholic Acid - metabolism; Lithocholic Acid - pharmacology; NF-kappa B - genetics; NF-kappa B - metabolism; Receptors, Calcitriol - drug effects; Receptors, Calcitriol - metabolism
• ISSN: 0960-0760
• DOI: 10.1016/j.jsbmb.2008.01.003

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.