It has been speculated that IL-1 genes play a crucial role in the genetic predisposition to duodenal ulcer upon H. pylori infection by modulating the host immune response. In the present study, 310 individuals from Eastern India were subjected to a case-control study to determine the IL1B and IL1RN risk genotypes to H. pylori mediated duodenal ulcer. An analysis of genotype frequency revealed a significantly higher frequency of IL1B -511TT (NT_022135.14:g.2302610C>T), OR=4.22 (95% CI=1.8-9.4) and -31CC (NT_022135.14:g.2302130C>T), OR=2.16 (95% CI 1.12-4.15) genotypes in H. pylori-infected individuals with duodenal ulcer compared to infected individuals with normal mucosa. Moreover, the T/C haplotype of IL1B -511 and IL1B -31 loci was present in a significantly higher frequency in H. pylori-infected duodenal ulcer patients than in infected controls (OR=2.47, CI=1.27-4.8). Quantitative analysis of the mucosal IL1B mRNA revealed that among H. pylori-infected individuals, carriers of the -31CC genotype had significantly lower IL1B transcript levels than carriers of the CT (P<0.001) and TT (P<0.001) genotypes, independently of disease status. An IL1B promoter activity assay showed that the promoter with -31T had a 10-fold increase in activity compared to the one with -31C. The IL1B promoter bearing the different combinations of both polymorphic loci showed an interaction between the -511 and -31 loci. Our results show that H. pylori-infected individuals with the -31CC genotype secrete less IL1B and are susceptible to duodenal ulcers. They also suggest that the allelic interaction between the -511 and -31 polymorphic sites determines the overall strength of the IL1B promoter.

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Background Helicobacter pylori elicited IL1B is one of the various modulators responsible for perturbation of acid secretion in gut. We have earlier reported that IL1B activated NFkB downregulates gastrin, a major modulator of acid secretion. However, we hypothesized that regulation of gastrin by IL1B would depend on the cell's ability to integrate inputs from multiple signaling pathways to generate appropriate biological response.Principal FindingIn this study, we report that IL1B induces Smad 7 expression by about 4.5 fold in gastric carcinoma cell line, AGS. Smad 7 resulted in transcriptional repression of gastrin promoter by about 6.5 fold when co -transfected with Smad 7 expression vector and gastrin-promoter luciferase in AGS cells. IL1B inhibited phosphorylation of Smad 3 and subsequently interfered with nuclear translocation of the positive Smad complex, thus occluding it off the gastrin promoter. IL1B promoter polymorphisms (-511T/-31C IL1B) are known to be associated with H. pylori associated gastro-duodenal ulcer. We observed that IL1B expressed from -31T promoter driven IL1B cDNA elicited 3.5 fold more Smad 7 than that expressed from the IL1B-31C variant in AGS cells. This differential activation of Smad 7 by IL1B promoter variants translated into differential downregulation of gastrin expression. We further analyzed Smad 7, NFkB, IL1B and gastrin expression in antral gut biopsy samples of patients with H. pylori associated duodenal ulcer and normal individuals. We observed that individuals with duodenal ulcer had significantly lower levels of IL1B, Smad 7, NFkB and corresponding higher level of gastrin expression.ConclusionPro-inflammatory cytokine IL1B repress gastrin expression by activating Smad 7 and subsequent inhibition of nuclear localization of Smad 3/4 complex. Polymorphic promoter variants of IL1B gene can modulate the IL1B expression which resulted in differential activation Smad 7 and consequent repression of gastrin expression, respectively. Analysis of H. pylori infected duodenal ulcer patient's gut biopsy samples also supported this observation.

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