Interferon gamma-signature transcript profiling and IL-23 upregulation in response to Helicobacter pylori infection

Unite de Pathogénie Bacterienne des Muqueuses, Institut Pasteur, Paris, France.
International journal of immunopathology and pharmacology (Impact Factor: 1.62). 01/2008; 21(3):515-26.
Source: PubMed

ABSTRACT Helicobacter pylori infection is the major cause of gastroduodenal pathologies including gastric cancer. The long persistence of bacteria and the type of immune and inflammatory response determine the clinical issue. In this study, the global gene expression profile after 6 and 12 months of H. pylori infection was investigated in the mouse stomach, using the Affymetrix GeneChip Mouse Expression Array A430. Genes related to the inflammatory and immune responses were focused. Levels of selected transcripts were confirmed by reverse transcription polymerase chain reaction. Twenty- five and nineteen percent of the differentially expressed genes observed at 6 and 12 months post-infection respectively, were related to immune response. They are characterized by an interferon (IFN)gamma-dependent expression associated to a T helper 1 (Th1) polarised response. In-depth analysis revealed that an up-regulation of IL-23p19, took place in the stomach of H. pylori infected-mice. Strong IL-23p19 levels were also confirmed in gastric biopsies from H. pylori-infected patients with chronic gastritis, as compared to healthy subjects. Our microarray analysis revealed also, a high decrease of H+K+-ATPase transcripts in the presence of the H. pylori infection. Association of gastric Th1 immune response with hypochlorhydria through the down-regulation of H+K+-ATPase contributes to the genesis of lesions upon the H. pylori infection. Our data highlight that the up-regulation of IL-23 and of many IFNgamma signature transcripts occur early on during the host response to H. pylori, and suggest that this type of immune response may promote the severity of the induced gastric lesions.

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    • "High throughput microarray technology provides a powerful tool for comprehensive gene analysis, already applied to assess gene expression patterns in both human samples and animal models of gastric disorders [7-16]. Although many researchers have focused on gene expression in H. pylori-treated gastric cell lines [17-19], results in cell culture do not necessarily correlate with expression of specific genes in the in vivo microenvironment featuring host immune responses and stromal-epithelial interactions in cancers. "
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    ABSTRACT: Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model. To find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6 J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis. The multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival. These results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior.
    BMC Gastroenterology 07/2013; 13(1):122. DOI:10.1186/1471-230X-13-122 · 2.37 Impact Factor
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    • "Atypia in the antrum and the fundus are also observed. Consistent with our previous findings (Vivas et al., 2008), USF1 and USF2 gene expression levels were one-third to one half and one-sixth to one half those in uninfected mice at 12 and 18 months post infection respectively (Fig. 2B). H. pylori infection decreases USF1/USF2-DNA binding to the E-box promoter region USF1 and USF2 bind to the E-box element present in the promoter region of genes (Corre and Galibert, 2005). "
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    ABSTRACT: Helicobacter pylori infection is associated with the development of gastric adenocarcinoma. Upstream stimulatory factors USF1 and USF2 regulate the transcription of genes related to immune response, cell cycle and cell proliferation. A decrease in their expression is observed in human gastric epithelial cells infected with H. pylori, associated to a lower binding to their DNA E-box recognition site as shown by electrophoretic mobility shift assay. DNA methylation leads to gene silencing. The treatment of cells with 5'-azacytidine, an inhibitor of DNA methylation, restored the USF1 and USF2 gene expression in the presence of infection. Using promoter PCR methylation assay, a DNA hypermethylation was shown in the promoter region of USF1 and USF2 genes, in infected cells. The inhibition of USF1 and USF2 expression by H. pylori and the DNA hypermethylation in their gene promoter region was confirmed in gastric tissues isolated from 12 to 18 months infected mice. Our study demonstrated the involvement of USF1 and USF2 as molecular targets of H. pylori and the key role of DNA methylation in their regulation. These mechanisms occurred in the context of metaplastic lesions, suggesting that alteration of USF1 and USF2 levels could participate in the promotion of neoplastic process during H. pylori infection.
    Cellular Microbiology 02/2010; 12(8):1124-33. DOI:10.1111/j.1462-5822.2010.01457.x · 4.92 Impact Factor
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    • "In H. pylori infection, a predominant activation of Th1 cells, with the production of IFN-g, IL-12, IL-18, IL-23 and TNFa , occurs in vivo in the stomach in human and animal models (Mohammadi et al., 1996; D'Elios et al., 1997; Luzza et al., 2000; Mattapallil et al., 2000; Rossi et al., 2000; Tomita et al., 2001; Vivas et al., 2008). Complex and fascinating mechanisms are responsible for the mucosal Th1 polarization (D'Elios et al., 1997, 2005; Del Giudice et al., 2001). "
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    ABSTRACT: Bronchial asthma and allergic diseases are orchestrated by T-cells producing T-helper type 2 (Th2) cytokines, such as interleukin-4 (IL-4) and IL-5, and are inhibited by Th1 responses. Helicobacter pylori has chronically infected the human population for c. 100,000 years and preferentially elicits a Th1 mucosal immune response with the production of interferon-gamma and IL-12. Among several bacterial factors, the neutrophil-activating protein of H. pylori (HP-NAP) not only plays a key role in driving Th1 inflammation but it is also able to inhibit Th2 responses in vitro and in vivo in allergic bronchial asthma, in humans and mice. Both systemic and mucosal administrations of HP-NAP are successful in reducing eosinophilia, immunoglobulin E and systemic Th2 cytokines at the bronchial level. Thus, these results identify HP-NAP as a candidate for novel strategies for the prevention and treatment of allergic diseases.
    FEMS Immunology & Medical Microbiology 03/2009; 56(1):1-8. DOI:10.1111/j.1574-695X.2009.00537.x · 3.08 Impact Factor
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