Interleukin-1β Promotes Gastric Atrophy Through Suppression of Sonic Hedgehog

Waghray, Meghna; Zavros, Yana; Saqui‐Salces, Milena; El–Zaatari, Mohamad; Alamelumangapuram, C. Bharath; Todisco, Andrea; Eaton, Kathryn A.; Merchant, Juanita L.

doi:10.1053/j.gastro.2009.10.043

Cited by 93 publications

(99 citation statements)

References 33 publications

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“…67 Gastric acid induces Shh gene expression. 56, , 68 69 Aberrant expression of Shh is involved in the pathogenesis of gastric diseases such as gastric atrophy, 70,71 hypergastrinemia and hyperproliferation of surface mucous cells. 72 All these studies will help us to better understand the molecular mechanism of gastric diseases and optimize the strategy of treatment.…”

Section: Activation Of the Hh Pathway In Gastric Cancermentioning

confidence: 99%

Activation of the hedgehog pathway in gastroesophageal cancers

Yang

Xie²,

Su³

2011

JST

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The hedgehog pathway is a major regulator for cell differentiation, tissue polarity and cell proliferation in embryonic development and homeostasis in adult tissue. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas, medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last two years in our understanding of hedgehog signaling activation in human gastroesophageal cancer, and their potential in clinical treatment with hedgehog pathway inhibitors.

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Section: Activation Of the Hh Pathway In Gastric Cancermentioning

confidence: 99%

Activation of the hedgehog pathway in gastroesophageal cancers

Yang

Xie²,

Su³

2011

JST

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“…Progressive fundic hyperplasia was also observed in other mouse models of inflammation, such as the stomach‐specific IL‐1 β ‐overexpressing mouse,27 after chronic IL‐11 exposure,25 in Helicobacter felis ‐infected mice,44 and in gastrin‐KO and omeprazole‐treated mice that develop gastric bacterial overgrowth 45. In these models, the inflammatory cytokines are believed to downregulate sonic hedgehog expression,45 an important parietal cell morphogen, leading to parietal cell demise and loss of gastric acidity 19, 43.…”

Section: Discussionmentioning

confidence: 77%

Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux

Liu

Riederer

et al. 2017

Acta Physiologica

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AimThis study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).MethodsWe assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH i of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR.Results CAIX‐knockout gastric surface epithelial cells showed significantly faster pH i decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months.ConclusionsWe propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO 2 and H2O, contributing to tight junction protection and gastric epithelial pH i regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.

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“…It is reported that individuals carrying the IL-1β and TNFα risk genotype are likely to suffer GC (27). IL-1β promotes gastric atrophy through suppression of Sonic Hedgehog (28). The upregulation of IL-1β, IL-8 and COX-2 in patients with chronic gastritis has a significant clinical implication in gastric carcinogenesis (29).…”

Section: Discussionmentioning

confidence: 99%

Effect of interleukin-1β and tumor necrosis factor α gene silencing on mouse gastric cancer cell proliferation and migration

et al. 2016

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Abstract. The aim of the present study was to investigate the effect of interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) gene co-silencing in mouse gastric cancer (GC) cells. Respectively, three pairs of liposome-encapsulated IL-1β and TNFα small interfering RNA (siRNA) were transfected into the mouse GC cell line MFC. The most effective siRNA, as identified by reverse transcription-polymerase chain reaction, was used for co-suppression of IL-1β and TNFα genes. The activities of cell proliferation, colony formation and migration were determined by the Cell Counting Kit 8 method, colony formation assay and Transwell assay, respectively. Protein array analysis was performed to identify the differentially expressed factors. The possible signaling pathways of the various factors targeting the genes were identified by pathway enrichment analysis using KOBAS 2.0. siRNA1 and siRNAc were the most effective interference sequences for IL-1β and TNFα, respectively. Following co-transfection of siRNA1 and siRNAc, the expression of IL-1β and TNFα was inhibited at the mRNA and protein levels, and the cell proliferation, colony forming and migration abilities were reduced (P<0.05). The expression of inflammatory factors, including chemokine ligand 5, cyclooxygenase-2, IL-6, transforming growth factor β, IL-17A, matrix metallopeptidase 9 and stromal cell-derived factor 1α were also inhibited (P<0.05). These factors are mainly involved in the rheumatoid arthritis pathway, the intestinal immune network for IgA production, the TNF signaling pathway and the inflammatory bowel disease pathway. IL-1β and TNFα gene silencing inhibits the proliferation and migration of MFC. The mechanisms may involve multiple inflammatory factors that participate in the signaling pathways of tumor tissue inflammation, the immune

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Interleukin-1β Promotes Gastric Atrophy Through Suppression of Sonic Hedgehog

Cited by 93 publications

References 33 publications

Activation of the hedgehog pathway in gastroesophageal cancers

Activation of the hedgehog pathway in gastroesophageal cancers

Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux

Effect of interleukin-1β and tumor necrosis factor α gene silencing on mouse gastric cancer cell proliferation and migration

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