IL1B Induced Smad 7 Negatively Regulates Gastrin Expression
IR@IICB: CSIR-Indian Institute of Chemical Biology, KolkataView Archive Info
IL1B Induced Smad 7 Negatively Regulates Gastrin
Datta De, Dipanjana
Dhali, G D
Molecular & Human Genetics
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 Finding: In 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
Conclusion: Pro-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.
Datta De, Dipanjana and Bhattacharjy, Sumana and Maitra, Meenakshi and Datta, Arindam and Choudhury, Abhijit and Dhali, G D and Roychoudhury, Susanta (2011) IL1B Induced Smad 7 Negatively Regulates Gastrin Expression. PLOS ONE, 6 (3).