Differential effects of deoxycholic acid and taurodeoxycholic acid on NF-kappa B signal transduction and IL-8 gene expression in colonic epithelial cells

Several effects of bile acids (BAs) on colonic epithelial cells (CECs) have been described, including induction of proliferation and apoptosis. Some of these effects are mediated through activation of the NF-kappa B transcriptional system. In this study, we investigated the molecular mechanisms unde...

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Published in:American journal of physiology: Gastrointestinal and liver physiology 2004-06, Vol.286 (6), p.G1000-G1008
Main Authors: Mühlbauer, M, Allard, B, Bosserhoff, A K, Kiessling, S, Herfarth, H, Rogler, G, Schölmerich, J, Jobin, C, Hellerbrand, C
Format: Article
Language:English
Subjects:
Bile Acids and Salts - pharmacology
Cells, Cultured
Colon - cytology
Colon - drug effects
Colon - metabolism
Deoxycholic Acid - pharmacology
Gene Expression - drug effects
Humans
Interleukin-8 - genetics
Interleukin-8 - metabolism
Intestinal Mucosa - cytology
Intestinal Mucosa - drug effects
Intestinal Mucosa - metabolism
NF-kappa B - metabolism
RNA, Messenger - metabolism
Signal Transduction - drug effects
Taurodeoxycholic Acid - pharmacology
Time Factors
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Summary:Several effects of bile acids (BAs) on colonic epithelial cells (CECs) have been described, including induction of proliferation and apoptosis. Some of these effects are mediated through activation of the NF-kappa B transcriptional system. In this study, we investigated the molecular mechanisms underlying the BA-induced gene expression in CECs. The human CEC line HT-29 and primary human CECs were treated with dilutions of salts of deoxycholic acid (DCA) and taurodeoxycholic acid (TDCA). NF-kappa B binding activity was analyzed with EMSA, RelA translocation with immunofluorescence, and I kappa B alpha- and RelA-phosphorylation with Western blot analysis. IL-8 mRNA and protein expression were assessed by quantitative PCR and ELISA. Functional impact of NF-kappa B activation was determined by blocking the proteasome activity with MG132 or by preventing IKK activity with a dominant-negative IKK beta delivered by adenoviral dominant-negative (dn) IKK beta (Ad5dnIKK beta). DCA and TDCA induced IL-8 expression in a dose- and time-dependent manner. It is interesting that DCA but not TDCA induced I kappa B alpha-phosphorylation, RelA translocation, and NF-kappa B binding activity. Accordingly, the proteasome inhibitor MG132 blocked DCA- but not TDCA-induced IL-8 gene expression. In contrast, TDCA-induced IL-8 gene expression correlated with enhanced RelA phosphorylation, which was blocked by Ad5dnIKK beta. Our data suggest that DCA-induced signal transduction mainly utilized the I kappa B degradation and RelA nuclear translocation pathway, whereas TDCA primarily induced IL-8 gene expression through RelA phosphorylation. These differences may have implications for the understanding of the pathophysiology of inflammation and carcinogenesis in the gut.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00338.2003