IL1B Induced Smad 7 Negatively Regulates Gastrin Expression

De, Dipanjana Datta; Bhattacharjya, Sumana; Maitra, Meenakshi; Datta, Asoke G.; Choudhury, Abhijit; Dhali, Gopal Krishna; Roychoudhury, Susanta

doi:10.1371/journal.pone.0014775

Cited by 14 publications

(14 citation statements)

References 27 publications

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“…Specifically, Datta et al . reported that GAST mRNA expression can be repressed by IL-1β via Smad7 or NFκB activation [36] , [37] . Therefore we tested whether IL-1β suppresses GAST gene expression.…”

Section: Resultsmentioning

confidence: 99%

Inflammation and Gli2 Suppress Gastrin Gene Expression in a Murine Model of Antral Hyperplasia

et al. 2012

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Chronic inflammation in the stomach can lead to gastric cancer. We previously reported that gastrin-deficient (Gast−/−) mice develop bacterial overgrowth, inflammatory infiltrate, increased Il-1β expression, antral hyperplasia and eventually antral tumors. Since Hedgehog (Hh) signaling is active in gastric cancers but its role in precursor lesions is poorly understood, we examined the role of inflammation and Hh signaling in antral hyperplasia. LacZ reporter mice for Sonic hedgehog (Shh), Gli1, and Gli2 expression bred onto the Gast−/− background revealed reduced Shh and Gli1 expression in the antra compared to wild type controls (WT). Gli2 expression in the Gast−/− corpus was unchanged. However in the hyperplastic Gast−/− antra, Gli2 expression increased in both the mesenchyme and epithelium, whereas expression in WT mice remained exclusively mesenchymal. These observations suggested that Gli2 is differentially regulated in the hyperplastic Gast−/− antrum versus the corpus and by a Shh ligand-independent mechanism. Moreover, the proinflammatory cytokines Il-1β and Il-11, which promote gastric epithelial proliferation, were increased in the Gast−/− stomach along with Infγ. To test if inflammation could account for elevated epithelial Gli2 expression in the Gast−/− antra, the human gastric cell line AGS was treated with IL-1β and was found to increase GLI2 but decrease GLI1 levels. IL-1β also repressed human GAST gene expression. Indeed, GLI2 but not GLI1 or GLI3 expression repressed gastrin luciferase reporter activity by ∼50 percent. Moreover, chromatin immunoprecipitation of GLI2 in AGS cells confirmed that GLI2 directly binds to the GAST promoter. Using a mouse model of constitutively active epithelial GLI2 expression, we found that activated GLI2 repressed Gast expression but induced Il-1β gene expression and proliferation in the gastric antrum, along with a reduction of the number of G-cells. In summary, epithelial Gli2 expression was sufficient to stimulate Il-1β expression, repress Gast gene expression and increase proliferation, leading to antral hyperplasia.

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Section: Resultsmentioning

confidence: 99%

Inflammation and Gli2 Suppress Gastrin Gene Expression in a Murine Model of Antral Hyperplasia

et al. 2012

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“…Hepcidin is an antimicrobial peptide involved in iron metabolism homeostasis and is a regulator of gastric acid secretion (47). Gastrin is a regulator of gastric acid secretion that is negatively regulated by IL-1-␤ through the activation of NFB (55). H,K-ATPase is the parietal cell enzyme that mediates acid secretion and is also transcriptionally repressed by NFB (56).…”

Section: Discussionmentioning

confidence: 99%

High Dietary Salt Intake Exacerbates Helicobacter pylori-Induced Gastric Carcinogenesis

et al. 2013

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Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pyloriinduced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA ؉ H. pylori strain or an isogenic cagA mutant strain and maintained the animals on a regular diet or a high-salt diet. At 4 months postinfection, gastric adenocarcinoma was detected in 100% of the WT-infected/highsalt-diet animals, 58% of WT-infected/regular-diet animals, and none of the animals infected with the cagA mutant strain (P < 0.0001). Among animals infected with the WT strain, those fed a high-salt diet had more severe gastric inflammation, higher gastric pH, increased parietal cell loss, increased gastric expression of interleukin 1␤ (IL-1␤), and decreased gastric expression of hepcidin and hydrogen potassium ATPase (H,K-ATPase) compared to those on a regular diet. Previous studies have detected upregulation of CagA synthesis in response to increased salt concentrations in the bacterial culture medium, and, concordant with the in vitro results, we detected increased cagA transcription in vivo in animals fed a high-salt diet compared to those on a regular diet. Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA ؉ H. pylori strains.

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“…IL1β inhibits gene expression of orexigenic ghrelin [ 32 ] and suppresses the production of gastric acid and gastrin [ 32 ]. However, it was shown recently that IL1β supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages [ 33 ]. Interestingly, high-fat-fed (HFF) mice exhibited a preferential increase of IL-1β concentration in portal compared to systemic blood [ 34 ], thus, indicating that the liver may differ in its IL-1β regulation from other perihearl tissues.…”

Section: Discussionmentioning

confidence: 99%

Expression of energy metabolism related genes in the gastric tissue of obese individuals with non-alcoholic fatty liver disease

et al. 2014

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BackgroundStomach is an integral part of the energy balance regulating circuit. Studies exploring the effects of cross-system changes in the energy homeostasis in stomach tissue are scarce. The proximity of the stomach to liver - the most common secondary target affected by obesity – suggests that these two organs are exposed to each other’s local secretion. Therefore, we aimed at expression profiling of energy metabolism associated genes in the gastric tissue of obese non-alcoholic fatty liver disease (NAFLD) patients.MethodsA total of 24 patients with histologically-proven NAFLD were included. In the gastric tissue, gene expression profiling of 84 energy metabolism associated genes was carried out.ResultsThe accumulation of the fat in the liver parenchyma is accompanied by downregulation of genes encoding for carboxypeptidase E (CPE) and Interleukin 1B (IL1B) in the gastric mucosa of same patient. In patients with high grade hepatic steatosis, Interleukin 1 beta encoding gene with anorexigenic function, IL1B was downregulated. The levels expression of 21 genes, including ADRA2B, CNR1 and LEP were significantly altered in the gastric tissue of NAFLD patients with hepatic inflammation. There were also indications of an increase in the opioid signaling within gastric mucosa that may results in a shift to proinflammatory environment within this organ and contribute to systemic inflammation and the pathogenic processes in hepatic parenchyma.ConclusionsWe have shown differential expression of energy metabolism associated genes in the gastric tissue of obese NAFLD patients. Importantly, these gene expression profiles are associated with changes in the hepatic parenchyma as reflected in increased scores for hepatic steatosis, inflammation, fibrosis and NASH. This study suggests the complex interplay of multiple organs in the pathogenesis of obesity-related complications such as NAFLD and provides further evidence supporting an important role for gastric tissue in promoting obesity-related complications.

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IL1B Induced Smad 7 Negatively Regulates Gastrin Expression

Cited by 14 publications

References 27 publications

Inflammation and Gli2 Suppress Gastrin Gene Expression in a Murine Model of Antral Hyperplasia

Inflammation and Gli2 Suppress Gastrin Gene Expression in a Murine Model of Antral Hyperplasia

High Dietary Salt Intake Exacerbates Helicobacter pylori-Induced Gastric Carcinogenesis

Expression of energy metabolism related genes in the gastric tissue of obese individuals with non-alcoholic fatty liver disease

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