Issn Print: 0192-0790
Publication Date: 2006/09/01
The activation of NF-κB by bile acids: the influence of acidity
J. Cronin; G. J. S. Jenkins; A. Alhamdani; S. H. Doak; A. P. Griffiths; J. M. Parry; J. N. Baxter
Excerpt
Barrett's oesophagus (BE) is a premalignant condition, where the normal squamous epithelium of the oesophagus has been replaced by abnormal columnar epithelium. Around 1% of adults in the UK have BE, and of these around 1% will progress to adenocarcinoma, via low grade and high grade dysplasia.In terms of numbers, it is the fastest growing cancer in the UK, and also one of the most aggressive, with fewer than 10% surviving for more than 5 years. The condition is strongly associated with the reflux of stomach contents up into the oesophagus and both gastric acid and bile acids have been reported as potential insults involved in the pathogenesis of BE. We have recently shown that physiological levels of the bile acid Deoxycholic acid (DCA) can induce transcriptional activation of Nuclear factor kappaB (NF-κB) in oesophageal cell lines and ex vivo biopsies. We have also shown that NF-κB activation is increasingly observed during the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's oesophagus. Hence bile induced NF-κB activation may represent an important molecular event in oesophageal carcinogenesis. Subsequent to activation by bile, NF-κB translocates to the nucleus and induces transcription of a set of genes including the pro-inflammatory cytokine IL-8 and NF-κB's inhibitor; IκB. Our studies have shown that activation of NF-κB by DCA is pH dependent: As the media becomes more acidic the upregulation of the IL-8 gene is greatly nullified. In contrast, acidified bile caused increased levels of IκB up-regulation. Increased IκB levels did not alter after treating the cells with acidic bile plus an NF-κB inhibitor; PDTC. Therefore, acidity has an effect on bile induced NF-κB activation. The observed independent behaviour of IκB expression levels may suggest an alternative pathway of IκB expression after acidic bile exposure.Chromatin immunoprecipitation (ChIP) assays to assess whether acidity causes IL-8/ IκB promoter binding, have shown that as the media becomes more acidic, bile induces less binding of NF-κB to the promoters of IκB and IL-8. Therefore, another signalling pathway appears to be involved in IκB expression and hence may interact with NF-κB signalling following acidic bile exposure.This research was funded in part by TENOVUS: the cancer charity, 43 The Parade, Cardiff, CF24 3AB, UK.
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