title: 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 NFkappaB and involvement of HDACs. An almost 3-fold increase in IL1B expression was observed when AGS cells were transfected with -31TIL1B expression plasmid in comparison to -31CIL1B. The -31TIL1B induced a 2-fold greater repression of the gastrin luciferase activity compared to -31CIL1B. This signaling of the -31TIL1B variant allele driven IL1B revealed an almost 1.5-fold greater expression of NFkappaB. 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 NFkappaB activation and gastrin expression.
authors.affiliation: Molecular and Human Genetics Division, Indian Institute of Chemical Biology, Raja S.C. Mullick Road, Kolkata, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Chakravorty
authors.forename: Dipanjana
authors.initials: D
authors.lastname: Datta De
authors.forename: Abhijit
authors.initials: A
authors.lastname: Choudhury
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013997:Time Factors; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D005755:Gastrins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D016328:NF-kappa B; C012589:trichostatin A; D014108:Tosylphenylalanyl Chloromethyl Ketone