IL1B promoter polymorphism regulates the expression of gastric acid stimulating hormone gastrin

Abstract

It is important to dissect the effect of the alternative alleles of a functional SNP on the entire biochemical pathway for the complete understanding of the mechanism of the manifestation of complex diseases. IL1B-511C > T and -31C > T promoter polymorphisms have been suggested as potential susceptibility loci for Helicobacter pylori associated gastroduodenal diseases. We report that altered expression of IL1B due to a specific polymorphism in its promoter modulates the expression of gastrin, an acid regulating hormone. Treatment of gastric carcinoma cells, AGS, with IL1B resulted in a 20-fold reduction in gastrin expression. Gastrin promoter assay showed that IL1B inhibits gastrin expression at the transcriptional level and part of this inhibitory process is mediated via activation of NFκB and involvement of HDACs. An almost 3-fold increase in IL1B expression was observed when AGS cells were transfected with -31T IL1B expression plasmid in comparison to -31C IL1B. The -31T IL1B induced a 2-fold greater repression of the gastrin luciferase activity compared to -31C IL1B. This signaling of the -31T IL1B variant allele driven IL1B revealed an almost 1.5-fold greater expression of NFκB. Thus, this study showed that a single base substitution at the -31 position of the IL1B promoter brought about differential expression of IL1B which differentially altered both NFκB activation and gastrin expression.