scholarly journals Helicobacter pylori–induced matrix metallopeptidase-10 promotes gastric bacterial colonization and gastritis

2019 ◽  
Vol 5 (4) ◽  
pp. eaau6547 ◽  
Author(s):  
Yi-pin Lv ◽  
Ping Cheng ◽  
Jin-yu Zhang ◽  
Fang-yuan Mao ◽  
Yong-sheng Teng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bacterial Colonization ◽  
Gastric Epithelium ◽  
Erk Pathway ◽  
Gastric Epithelial Cells ◽  
Zonula Occludens ◽  
Matrix Metallopeptidase ◽  
Zonula Occludens 1 ◽  
H Pylori

The interaction between gastric epithelium and immune response plays key roles in H. pylori–associated pathology. We demonstrated a procolonization and proinflammation role of MMP-10 in H. pylori infection. MMP-10 is elevated in gastric mucosa and is produced by gastric epithelial cells synergistically induced by H. pylori and IL-22 via the ERK pathway. Human gastric MMP-10 was correlated with H. pylori colonization and the severity of gastritis, and mouse MMP-10 from non–BM-derived cells promoted bacteria colonization and inflammation. H. pylori colonization and inflammation were attenuated in IL-22−/−, MMP-10−/−, and IL-22−/−MMP-10−/− mice. MMP-10–associated inflammation is characterized by the influx of CD8+ T cells, whose migration is induced via MMP-10–CXCL16 axis by gastric epithelial cells. Under the influence of MMP-10, Reg3a, E-cadherin, and zonula occludens–1 proteins decrease, resulting in impaired host defense and increased H. pylori colonization. Our results suggest that MMP-10 facilitates H. pylori persistence and promotes gastritis.

Intrafamilial Infection of Helicobacter Pylori: Abnormal Gastric Epithelial Cells, Pedestal-Rich H. Pylori Adherence, and a Gene Mutation in a Child with Protein-Losing Gastroenteropathy

2019 ◽  
Vol 2 (3) ◽  
pp. 83-99
Author(s):  
T.W. Wan ◽  
O. Khokhlova ◽  
W. Higuchi ◽  
I. Protasova ◽  
Olga V. Peryanova ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Epithelial Cells ◽  
Gene Mutation ◽  
Virulence Factor ◽  
East Asian ◽  
Gastric Epithelium ◽  
Gastric Epithelial Cells ◽  
H Pylori

Abstract Helicobacter pylori, one of the most prevalent human pathogens, colonizes the gastric mucosa and is associated with gastric diseases, such as gastritis and peptic ulcers, and is also a bacterial risk factor for gastric cancer. Cytotoxin-associated gene A (CagA) protein, a major virulence factor of H. pylori, is phosphorylated in cells at its Glu-Pro-IIe-Tyr-Ala (EPIYA) motif and is considered to trigger gastric cancer. CagA is classified into two forms, Western CagA with EPIYA-ABC and East Asian CagA with EPIYA-ABD, with the latter associated with a high risk of developing gastric cancer. CagA causes morphological transformation of cells, yielding the “hummingbird” phenotype in AGS cells and possibly membranous pedestals in the gastric epithelium, albeit rarely. H. pylori adherence to the gastric mucosa is not yet fully understood. Here, we describe an intrafamilial infection case of H. pylori, focusing on the gastric epithelium, H. pylori adherence, and a gene mutation in a child with protein-losing gastroenteropathy (characterized by excessive loss of plasma proteins into the gastrointestinal tract). H. pylori, which also infected family members (mother and father), was genetically a single clone with the virulence genes of an East Asian type. The patient’ gastric mucosa exhibited some unique features. Endoscopy revealed the presence of protein plugs on the mucosal surface, which were immunoelectrophoretically similar to serum proteins. Electron microscopy revealed abnormal gastric epithelial cells, totally covered with the secretions or possessing small swollen structures and irregular microvilli. The patient’s H. pylori infection was characterized by frequently occurring thick pedestals, formed along adherent H. pylori. The serum protein level returned to normal and the protein plugs disappeared after the successful eradication of H. pylori, albeit with lag periods for healing. He had a mutation in the OCRL1 gene, associated with Dent disease (asymptomatic proteinuria). Thus, in the patient’s gastric mucosa, we found the abnormal gastric epithelial cells, which may be caused by an OCRL1 mutation or H. pylori, and pedestal-rich H. pylori infection, possibly caused by a higher level of action of CagA in the abnormal epithelial cells. The data suggests a novel H. pylori virulence factor associated with “excessive plasma protein release”.

scholarly journals Regulation of Interleukin-6 Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

2005 ◽  
Vol 16 (10) ◽  
pp. 4954-4966 ◽  
Author(s):  
Hong Lu ◽  
Jeng Yih Wu ◽  
Takahiko Kudo ◽  
Tomoyuki Ohno ◽  
David Y. Graham ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Signal Transduction Pathway ◽  
Dominant Negative ◽  
Gastric Epithelium ◽  
Luciferase Reporter ◽  
Gastric Epithelial Cells ◽  
Luciferase Reporter Gene ◽  
Mobility Shift ◽  
H Pylori ◽  
Cag Pai

The regulation of Helicobacter pylori induced interleukin (IL)-6 in the gastric epithelium remains unclear. Primary gastric epithelial cells and MKN28 cells were cocultured with H. pylori and its isogenic cag pathogenicity island (PAI) mutant and/or oipA mutants. H. pylori infection-induced IL-6 mRNA expression and IL-6 protein production, which was further enhanced by the cag PAI and OipA. Luciferase reporter gene assays and electrophoretic mobility shift assays showed that full IL-6 transcription required binding sites for nuclear factor-κB (NF-κB), cAMP response element (CRE), CCAAT/enhancer binding protein (C/EBP), and activator protein (AP)-1. The cag PAI and OipA were involved in binding to NF-κB, AP-1, CRE, and C/EBP sites. The cag PAI activated the extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) pathways; OipA activated the p38 pathway. Transfection of dominant negative G-protein confirmed roles for Raf, Rac1, and RhoA in IL-6 induction. Overall, the cag PAI-related IL-6 signal transduction pathway involved the Ras/Raf/MEK1/2/ERK/AP-1/CRE pathway and the JNK/AP-1/CRE pathway; the OipA-related pathway is p38/AP-1/CRE and both the cag PAI and OipA appear to be involved in the RhoA/Rac1/NF-κB pathway. Combination of different pathways by the cag PAI and OipA will lead to the maximum IL-6 induction.

Human Gastric Epithelium Produces IL-4 and IL-4δ2 Isoform Only upon Helicobacter Pylori Infection

2007 ◽  
Vol 20 (4) ◽  
pp. 809-818 ◽  
Author(s):  
B. Orsini ◽  
J.R. Vivas ◽  
B. Ottanelli ◽  
A. Amedei ◽  
E. Surrenti ◽  
...  
Keyword(s):  
Immune Response ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Mrna Expression ◽  
Healthy Subjects ◽  
Fine Tuning ◽  
Gastric Epithelium ◽  
Gastric Epithelial Cells ◽  
H Pylori ◽  
Cag Pai

Recent evidence suggests that interleukin-4 (IL-4) is related to mucosal tolerance by which an injurious immune response is prevented, suppressed or shifted to a non-injurious response. We investigated the expression of IL-4 and its splice variant isoform IL-4δ2 in gastric epithelial cells of healthy subjects and gastritis patients infected with Helicobacter pylori (H. pylori) with or without the cag pathogenicity island ( cag-PAI). IL-4 and IL-4δ2 mRNAs were evaluated in microdissected gastric epithelium and in AGS cell lines co-cultured with H. pylori B128 or SSI strains. IL-4 mRNA was consistently detected in microdissected gastric epithelial cells from healthy subjects. The IL-4 mRNA expression was low in H. pylori-infected patients, and markedly reduced in cag-PAI-positive ones. IL-4δ2 mRNA was expressed on gastric epithelium of H. pylori-infected patients, but not in healthy subjects. The IL-452 expression was lower in cag-PAI-positive than in cag-PAI-negative H. pylori infected patients. AGS cells also produced IL-4 mRNA upon SSI strain stimulation, whereas IL-4δ2 mRNA expression was detected in AGS co-cultured with either SSI or B128 strains. An inverse correlation was documented between IL-4 and IL-482 mRNA expression by microdissected gastric epithelial cells and the score of gastritis. IL-4, but not IL-452, is expressed by gastric epithelium of healthy subjects, whereas IL-452 and lesser IL-4 mRNA are detectable in the gastric epithelium of H. pylori-infected patients. Data suggest that gastric epithelial cells might regulate the balance between tolerance and immune response by the fine tuning of IL-4 and IL-4δ2 expression.

Helicobacter pylori antigens, acetylsalicylic acid, LDL and 7-ketocholesterol - their potential role in destabilizing the gastric epithelial cell barrier. An in vitro model of Kato III cells.

2015 ◽  
Vol 63 (1) ◽  
Author(s):  
Adrian Gajewski ◽  
Eliza Mnich ◽  
Karol Szymański ◽  
Krzysztof Hinc ◽  
Michał Obuchowski ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Acetylsalicylic Acid ◽  
Gastric Epithelium ◽  
Lipid Transport ◽  
Cholesterol Oxidation ◽  
Tetrazolium Salt ◽  
Gastric Epithelial Cells ◽  
Cell Nuclei ◽  
Dapi Staining ◽  
H Pylori

Colonization of gastric tissue in humans by H. pylori Gram-negative bacteria initiates gastric and duodenal ulcers and even gastric cancers. Infections promote inflammation and damage to gastric epithelium which might be followed by the impairment of its barrier function. The role of H. pylori components in these processes has not been specified. H. pylori cytotoxicity may potentially increase in the milieu of anti-inflammatory drugs including acetylsalicylic acid (ASA). The lipid transport-associated molecule such as low density lipoprotein (LDL), which is a classic risk factor of coronary heart disease (CHD) and 7-ketocholesterol (7-kCh) a product of cholesterol oxidation, which may occur during the oxidative stress in LDL could also be considered as pro-inflammatory. The aim of this study was to evaluate the cytotoxicity of H. pylori antigens, ASA, LDL and 7-kCh towards Kato III gastric epithelial cells, on the basis of the cell ability to reduce tetrazolium salt (MTT) and morphology of cell nuclei assessed by 4',6-diamidino-2-phenylindole (DAPI) staining. Kato III cells were stimulated for 24 h, at 37°C and 5% CO2, with H. pylori antigens: cytotoxin associated gene A (CagA) protein, the urease A subunit (UreA), lipopolysaccharide (LPS) and ASA, LDL or 7-kCh. H. pylori LPS, ASA, LDL and 7-kCh, but not H. pylori glycine acid extract (GE), demonstrated cytotoxicity against Kato III cells, which was related to a diminished percentage of MTT reducing cells and to an increased cell population with the signs of DNA damage. The results suggest that damage to gastric epithelial cells can be induced independently by H. pylori antigens, ASA and endogenous lipid transport-associated molecules. During H. pylori infection in vivo, especially in CHD patients, synergistic or antagonistic interactions between these factors might possibly influence the disease course. Further study is necessary to explain these potential effects.

Persistence ofHelicobacter pyloriVacA toxin and vacuolating potential in cultured gastric epithelial cells

1998 ◽  
Vol 275 (4) ◽  
pp. G681-G688 ◽  
Author(s):  
Patrizia Sommi ◽  
Vittorio Ricci ◽  
Roberto Fiocca ◽  
Vittorio Necchi ◽  
Marco Romano ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Neutral Red ◽  
Gastric Epithelium ◽  
Broth Culture ◽  
Gastric Epithelial Cells ◽  
Lysosomal Compartment ◽  
Quantitative Immunofluorescence ◽  
Membrane Bound ◽  
H Pylori ◽  
Red Dye

The vacuolating toxin A (VacA) is one of the most important virulence factors in Helicobacter pylori-induced damage to human gastric epithelium. Using human gastric epithelial cells in culture and broth culture filtrate from a VacA-producing H. pylori strain, we studied 1) the delivery of VacA to cells, 2) the localization and fate of internalized toxin, and 3) the persistence of toxin inside the cell. The investigative techniques used were neutral red dye uptake, ultrastructural immunocytochemistry, quantitative immunofluorescence, and immunoblotting. We found that VacA 1) is delivered to cells in both free and membrane-bound form (i.e., as vesicles formed by the bacterial outer membrane), 2) localizes inside the endosomal-lysosomal compartment, in both free and membrane-bound form, 3) persists within the cell for at least 72 h, without loss of vacuolating power, which, however, becomes evident only when NH4Cl is added, and 4) generally does not degrade into fragments smaller than ∼90 kDa. Our findings suggest that, while accumulating inside the endosomal-lysosomal compartment, a large amount of VacA avoids the main lysosomal degradative processes and retains its apparent molecular integrity.

scholarly journals Helicobacter pylori Binds to CD74 on Gastric Epithelial Cells and Stimulates Interleukin-8 Production

2005 ◽  
Vol 73 (5) ◽  
pp. 2736-2743 ◽  
Author(s):  
Ellen J. Beswick ◽  
David A. Bland ◽  
Giovanni Suarez ◽  
Carlos A. Barrera ◽  
Xuejung Fan ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Inflammatory Responses ◽  
Surface Expression ◽  
Class Ii ◽  
Gastric Epithelium ◽  
Host Responses ◽  
Gastric Epithelial Cells ◽  
Class Ii Mhc ◽  
H Pylori

ABSTRACT The pathogenesis associated with Helicobacter pylori infection requires consistent contact with the gastric epithelium. Although several cell surface receptors have been suggested to play a role in adhesion, the bacterium-host interactions that elicit host responses are not well defined. This study investigated the interaction of H. pylori with the class II major histocompatibility complex (MHC)-associated invariant chain (Ii; CD74), which was found to be highly expressed by gastric epithelial cells. Bacterial binding was increased when CD74 surface expression was increased by gamma interferon (IFN-γ) treatment or by fibroblast cells transfected with CD74, while binding was decreased by CD74 blocking antibodies, enzyme cleavage of CD74, and CD74-coated bacteria. H. pylori was also shown to bind directly to affinity-purified CD74 in the absence of class II MHC. Cross-linking of CD74 and the engagement of CD74 were verified to stimulate IL-8 production by unrelated cell lines expressing CD74 in the absence of class II MHC. Increased CD74 expression by cells increased IL-8 production in response to H. pylori, and agents that block CD74 decreased these responses. The binding of H. pylori to CD74 presents a novel insight into an initial interaction of H. pylori with the gastric epithelium that leads to upregulation of inflammatory responses.

TRPV4-Mediated Epithelial Junction Disruption in Allergic Rhinitis Triggered by House Dust Mites

2020 ◽  
pp. 194589242096416
Author(s):  
Kijeong Lee ◽  
Junhyoung Byun ◽  
Byoungjae Kim ◽  
Jiwoo Yeon ◽  
Junhu Tai ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
House Dust ◽  
Nasal Epithelial Cells ◽  
Zonula Occludens ◽  
Dust Mite ◽  
Cultured Epithelial Cells ◽  
Junctional Protein ◽  
Der P 1 ◽  
Zonula Occludens 1

Background Epithelial barrier disruption is a crucial feature of allergic rhinitis (AR). Previous reports have indicated the role of transient receptor potential vanilloid (TRPV) 4 in regulating the intercellular junctions in various cells. However, the role of TRPV4 and its regulation by T helper 2 cell cytokines in the epithelial cells of patients with AR remains unclear. Objective We aimed to elucidate the expression of TRPV4 in nasal epithelial cells and its cytokine-induced regulation, and to reveal its role in house dust mite-induced junction disruption in AR. Methods The expression of TRPV4 in nasal epithelial cells was measured using real-time polymerase chain reaction, western blot, and immunohistochemical assays, and the expression levels were compared between the patients with AR and healthy controls. Altered expression of TRPV4 was induced in cultured nasal epithelial cells by stimulation of interleukin (IL) 4, IL-13, and tumor necrosis factor alpha. In addition, expression of E-cadherin and zonula occludens 1 was induced in Der p 1-stimulated epithelial cells by treatment with either a TRPV4 agonist (GSK1016790A) or a TRPV4 antagonist (RN1734). Results TRPV4 expression was increased in epithelial cells harvested from the affected turbinates compared to those from the normal turbinates. The stimulation of cultured epithelial cells with IL-4 and IL-13 resulted in TRPV4 upregulation. Additionally, E-cadherin and zonula occludens 1 expression levels decreased in the cultured epithelial cells treated with GSK1016790A after stimulation with Der p 1, whereas Der p 1 stimulation alone showed no effect on junctional protein expression. Conclusions Increased TRPV4 expression occurred in epithelial cells harvested from patients with AR and epithelial cells stimulated by Th2 cytokines. Decreased junctional protein expression in epithelial cells after the stimulation by house dust mite allergen with TRPV4 agonist indicates a possible role of TRPV4 in the pathogenesis of allergen-induced epithelial barrier disruption in AR.

scholarly journals Induction of Monocyte Chemoattractant Protein 1 byHelicobacter pylori Involves NF-κB

2001 ◽  
Vol 69 (3) ◽  
pp. 1280-1286 ◽  
Author(s):  
Naoki Mori ◽  
Atsuhisa Ueda ◽  
Romas Geleziunas ◽  
Akihiro Wada ◽  
Toshiya Hirayama ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Gene Transcription ◽  
Gastric Epithelium ◽  
Luciferase Reporter ◽  
Gastric Epithelial Cells ◽  
Distal Enhancer ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
H Pylori

ABSTRACT Helicobacter pylori stimulates secretion of monocyte chemoattractant protein 1 (MCP-1) from gastric epithelial cells. Secretion of this chemokine may be instrumental in monocyte infiltration of the gastric epithelium that characterizes H. pylori gastritis. The aim of this study was to identify the mechanism by which H. pylori induces MCP-1 production. Induction of MCP-1 mRNA was assessed by reverse transcription-PCR. We used luciferase reporter assays to monitor activation of the MCP-1 gene promoter and electrophoretic mobility shift assays to explore binding of transcription factors to this promoter. H. pyloriinfection increased MCP-1 mRNA expression from gastric epithelial cells. Induction of MCP-1 mRNA relies on an intact cagpathogenicity island. We identified two closely spaced NF-κB-binding sites within the MCP-1 distal enhancer as required for H. pylori-induced MCP-1 gene transcription. H. pyloriinfection led to the specific activation of NF-κB complexes containing p50 and p65. Kinase-deficient mutants of NF-κB-inducing kinase (NIK) and IκB kinases (IKK) caused suppression of MCP-1 distal enhancer-dependent reporter activity following H. pyloriinfection. H. pylori infection induces the activation of NF-κB via the NIK-IKK signaling complex, leading to MCP-1 gene transcription in gastric epithelial cells.

scholarly journals Helicobacter pylori Infection Induces Interleukin-8 Receptor Expression in the Human Gastric Epithelium

2003 ◽  
Vol 71 (6) ◽  
pp. 3357-3360 ◽  
Author(s):  
Fredrik Bäckhed ◽  
Elisabeth Torstensson ◽  
Delphine Seguin ◽  
Agneta Richter-Dahlfors ◽  
Bachra Rokbi
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Gastric Biopsy ◽  
Receptor Expression ◽  
Interleukin 8 ◽  
Gastric Epithelium ◽  
Epithelial Cell Line ◽  
Gastric Epithelial Cells ◽  
H Pylori

ABSTRACT The gastric pathogen Helicobacter pylori is known to activate multiple proinflammatory signaling pathways in epithelial cells. In this study, we addressed the question of whether expression of the interleukin-8 receptors IL-8RA (CXCR1) and IL-8RB (CXCR2) is upregulated in H. pylori-infected human gastric biopsy samples. Biopsy samples from patients infected with H. pylori strains harboring the cag pathogenicity island (PAI) expressed larger amounts of both receptors. In addition, IL-8RB expression was induced in the gastric epithelial cell line AGS upon infection with a clinical isolate containing the cag PAI, while a strain lacking the cag PAI did not. Our finding suggests that gastric epithelial cells express IL-8R in response to H. pylori infection.

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