Lithocholic acid down-regulation of NF-kappaB activity through vitamin D receptor in colonic cancer cells.
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.
Sun
Jun
J
Department of Medicine, Gastroenterology and Hepatology, University of Rochester, Rochester, NY 14642, USA. jun_sun@umrc.rochester.edu
Mustafi
Reba
R
Cerda
Sonia
S
Chumsangsri
Anusara
A
Xia
Yinglin Rick
YR
Li
Yan Chun
YC
Bissonnette
Marc
M
D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002999:Clone Cells; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D008095:Lithocholic Acid / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000187:drug effects* / Q000378:metabolism
D016328:NF-kappa B; D018167:Receptors, Calcitriol; D008095:Lithocholic Acid