Low pH and <i>Helicobacter pylori</i> increase nuclear factor kappa B binding in gastric epithelial cells: A common pathway for epithelial cell injury?

O’Toole, Dermot; Abdel-Latif, Mohamed; Long, Aideen; Windle, Henry J.; Murphy, Anne M.; Bowie, Andrew; O’Neill, Luke A. J.; Weir, Donald G.; Kelleher, Dermot

doi:10.1002/jcb.20539

Cited by 17 publications

(19 citation statements)

References 45 publications

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“…The level of binding of H. heilmannii bacteria to gastric epithelial cells was higher at pH 7 than at pH 2. This is consistent with the physiological pH gradient in the stomach, ranging from pH 1 to 2 in the gastric lumen to pH 6 to 7 at the epithelial cell surface (49)(50)(51). Following this theory, we would expect better binding to human gastric mucins at pH 2, since they are located in the acidic lumen of the stomach.…”

Section: Discussionsupporting

confidence: 82%

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

et al. 2016

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h Helicobacter heilmannii naturally colonizes the stomachs of dogs and cats and has been associated with gastric disorders in humans. Nine feline Helicobacter strains, classified as H. heilmannii based on ureAB and 16S rRNA gene sequences, were divided into a highly virulent and a low-virulence group. The genomes of these strains were sequenced to investigate their phylogenetic relationships, to define their gene content and diversity, and to determine if the differences in pathogenicity were associated with the presence or absence of potential virulence genes. The capacities of these helicobacters to bind to the gastric mucosa were investigated as well. Our analyses revealed that the low-virulence strains do not belong to the species H. heilmannii but to a novel, closely related species for which we propose the name Helicobacter ailurogastricus. Several homologs of H. pylori virulence factors, such as IceA1, HrgA, and jhp0562-like glycosyltransferase, are present in H. heilmannii but absent in H. ailurogastricus. Both species contain a VacA-like autotransporter, for which the passenger domain is remarkably larger in H. ailurogastricus than in H. heilmannii. In addition, H. ailurogastricus shows clear differences in binding to the gastric mucosa compared to H. heilmannii. These findings highlight the low-virulence character of this novel Helicobacter species. Helicobacter pylori is considered one of the most successful human pathogens. Infection with this agent has been associated with a wide range of gastric disorders. However, H. pylori is not the only Helicobacter species causing gastric disease in humans. Helicobacter heilmannii (sensu stricto), a zoonotic bacterium naturally colonizing the stomachs of cats and dogs, has been associated with gastritis, peptic and duodenal ulcers, and mucosa-associated lymphoid tissue (MALT) lymphoma in humans (1-6). This Helicobacter species is highly prevalent in the stomachs of clinically healthy cats and dogs as well as in those of animals showing chronic active gastritis (1, 4). Its pathogenic significance in these animals remains unclear and is probably strain dependent or related to host differences (1).Little information is available regarding the pathogenesis of H. heilmannii infections in humans (1, 7). A recent experimental infection study, using Mongolian gerbils as an in vivo model to study Helicobacter-related gastric pathology in humans, investigated the colonization capacities and virulence of nine different Helicobacter strains (8). These helicobacters had been isolated from the gastric mucosae of stray cats and had been classified as H. heilmannii on the basis of the ureAB and 16S rRNA gene sequences (9). At 9 weeks postinfection, the induction of an antrum-dominant chronic active gastritis associated with the formation of lymphocytic aggregates and upregulation of the proinflammatory cytokine interleukin 1␤ (IL-1␤) was shown for seven strains. However, differences in the expression of IL-1␤ were noted, together with differences in the intensity of the obser...

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Section: Discussionsupporting

confidence: 82%

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

et al. 2016

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“…Hypochlorhydria provokes superficial gastritis, which may progress to atrophic gastritis, intestinal metaplasia, dysplasia, and eventually carcinoma3–5. The mechanisms underlying H. pylori -mediated transient hypochorhydria are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori CagL Activates ADAM17 to Induce Repression of the Gastric H, K-ATPase α Subunit

et al. 2010

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Background & Aims Infection with H. pylori represses expression of the gastric H, K-ATPase α subunit (HKα), which could contribute to transient hypochlorhydria. CagL, a pilus protein component of the H. pylori type IV secretion system, binds to the integrin α5β1 to mediate translocation of virulence factors into the host cell and initiate signaling. α5β1 binds ADAM17, a metalloenzyme that catalyzes ectodomain shedding of receptor tyrosine kinase ligands. We investigated whether H. pylori-induced repression of HKα is mediated by CagL activation of ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF). Methods HKα promoter and ADAM17 activity were measured in AGS gastric epithelial cells transfected with HKα promoter-reporter constructs or ADAM17-specific small interfering (si)RNAs and infected with H. pylori. HB-EGF secretion was measured by ELISA analysis and ADAM17 interaction with integrins were investigated by co-immunoprecipitation analyses. Results Infection of AGS cells with wild-type H. pylori or an H. pylori cagL-deficient isogenic mutant that also contained a wild-type version of cagL (P12ΔcagL/cagL) repressed HKα promoter-Luc reporter activity and stimulated ADAM17 activity. Both responses were inhibited by point mutations in the NF-κB binding site of HKα or by infection with P12ΔcagL. siRNA-mediated silencing of ADAM17 in AGS cells inhibited the repression of wild-type HKα promoter and reduced ADAM17 activity and HB-EGF production, compared to controls. Coimmunoprecipitation studies of AGS lysates showed that wild-type H. pylori disrupted ADAM17–α5β1 complexes. Conclusions During acute H. pylori infection, CagL dissociates ADAM17 from the integrin α5β1 and activates ADAM17-dependent, NF-κB–mediated repression of HKα. This might contribute to transient hypochlorhydria in patients with H. pylori infection.

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“…There is increasing evidence indicating that an acidic environment contributes to the regulation of expression of many genes during the inflammatory process. Previously, we demonstrated that acid induces NF-kB and AP-1 binding activities in gastric epithelial cells and this induction was mediated through MEK1-ERK1/2 dependent signaling pathways [O'Toole et al, 2005]. In this study, we have demonstrated that lowering the extracellular pH from 7.4 (resting pH of the medium) to pH 6.0 activates Egr-1 transcription factor in AGS cells.…”

Section: Discussionmentioning

confidence: 77%

“…Many tumors have a relatively acidic extracellular pH, although the intracellular pH of tumor cells remains normal due to the efficient maintenance of a large proton gradient across the membrane. O'Toole et al [2005] demonstrated that AGS cells exposed to acidic conditions can regulate their intracellular pH. It is known that the stomach is protected from the deleterious effect of gastric acid by several mechanisms [Bhaskar et al, 1992].…”

Section: Discussionmentioning

confidence: 98%

“…We have demonstrated that exposure of gastric epithelial cells to acidic conditions results in increased NF-kB and AP-1 DNA-binding activities [O'Toole et al, 2005]. Other investigators have shown that exposure of macrophages to external acidic environments leads to increased NF-kB binding activity and, further, that this activity was inhibited by treatment with the antioxidants pyrrolidine dithiocarbamate or N-acetyl-leucinyl-norleucinol [Bellocq et al, 1998].…”

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confidence: 97%

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A new mechanism of gastric epithelial injury induced by acid exposure: The role of Egr‐1 and ERK signaling pathways

Abdel-Latif

Windle

Davies

et al. 2009

J of Cellular Biochemistry

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The molecular mechanisms by which gastric acid causes epithelial injury in the stomach and initiates an inflammatory reaction are poorly understood. We aimed in the present study to investigate the role of the early growth response gene Egr-1 and ERK in gastric epithelial cells following acid exposure, and the signaling pathways involved. Western blotting was used to assess Egr-1 protein levels in AGS cells. A quantitative measurement of acid-induced Egr-1 and ERK translocation was performed using a high content analysis approach. Egr-1 functionality was assessed by transient transfection with Egr-1 antisense oligonucleotide. Exposure of AGS cells to acidic conditions induced Egr-1 protein expression in a pH- and time-dependent manner. Egr-1 expression was markedly increased as the pH was reduced from pH 7.4 to 6.4. High content analysis of Egr-1 activation showed acid-induced Egr-1 nuclear translocation; a maximum observed at 1-2 h followed by a decline to basal levels beyond 4 h. Acidic pH also activated ERK1/2 phosphorylation, whereas ERK1/2 inhibitors PD98059 and U0216 blocked both acid-induced Egr-1 and ERK translocation and expression. Moreover, acid exposure up-regulated VEGF expression, which was inhibited by the Egr-1 antisense oligonucleotide. Our results also demonstrate that exposure to acid induces Egr-1 via MEK-ERK1/2 pathway. These data suggest that Egr-1 activation might play a crucial role in gastric mucosal inflammation and associated epithelial injury.

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Low pH and Helicobacter pylori increase nuclear factor kappa B binding in gastric epithelial cells: A common pathway for epithelial cell injury?

Cited by 17 publications

References 45 publications

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

Helicobacter pylori CagL Activates ADAM17 to Induce Repression of the Gastric H, K-ATPase α Subunit

A new mechanism of gastric epithelial injury induced by acid exposure: The role of Egr‐1 and ERK signaling pathways

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