Modulation of Innate Cytokine Responses by Products of<i>Helicobacter pylori</i>

Meyer, Frank; Wilson, Keith T.; James, Stephen P.

doi:10.1128/iai.68.11.6265-6272.2000

Cited by 79 publications

(68 citation statements)

References 46 publications

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“…The presence of H. pylori in the gastric mucosa is associated with strong IL-12 production 36 and the presence of large numbers of Th1 cells. 37 Differentiation of naive T cells into activated Th1 cells requires the presence of IL-12, which is predominantly produced by macrophages rather than epithelial cells. Thus, it is likely that the H. pylori-positive macrophages within the lamina propria contribute to the accumulation of H. pylori-specific CD4 þ T cells by the strong IL-12 production of these macrophages.…”

Section: Intestinal Metaplasiamentioning

confidence: 99%

Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes

Ito

Kobayashi

Uchida

et al. 2008

Laboratory Investigation

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Helicobacter pylori has been considered to be non-invasive and to rarely infiltrate the gastric mucosa, even though there is an active Th1 immune response in the lamina propria of the H. pylori-infected stomach. To elucidate whether H. pylori invades the lamina propria and translocates to the gastric lymph nodes, we examined H. pylori in formalin-fixed and paraffin-embedded tissue sections of stomach and gastric lymph nodes obtained from 51 cancer patients using real-time PCR and immunohistochemistry (IHC) with a novel anti-H. pylori monoclonal antibody that recognizes lipopolysaccharides. Fresh gastric lymph nodes were used to culture for H. pylori. In 46 patients with H. pylori in the stomach, the bacterium was found in the lymph nodes from 21 patients by culture, 37 patients by PCR, and 29 patients by IHC. H. pylori captured by macrophages was found in the lamina propria of 39 patients. In the lymph nodes, the bacterium was found in many macrophages and a few interdigitating dendritic cells at the paracortical areas. H. pylori was also found in the intracellular canaliculi of parietal cells in 21 patients, but intracytoplasmic invasion into gastric epithelial cells was not identified. When compared to the commercially available anti-H. pylori antibodies, the novel antibody showed the highest sensitivity to detect H. pylori-positive macrophages, whereas no difference was found for H. pylori in the mucous layer. The H. pylori-positive macrophages in the lamina propria correlated with chronic gastritis as well as translocation of such cells to the lymph nodes. These results suggest that H. pylori-induced gastric epithelial damage allows the bacteria to invade the lamina propria and translocate to the gastric lymph nodes, which may chronically stimulate the immune system. The bacteria captured by macrophages, whether remaining alive or not, may contribute to the induction and development of H. pylori-induced chronic gastritis.

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Section: Intestinal Metaplasiamentioning

confidence: 99%

Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes

Ito

Kobayashi

Uchida

et al. 2008

Laboratory Investigation

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“…Recombinant H. pylori urease was obtained and used as described (2,19). Monoclonal anti-PGE 2 Ab 2B5 and MOPC21 isotype-matched (IgG) control Ab were provided by S. J. Mnich and J. P. Portanova (G. D. Searle, St. Louis, MO); 1.5 g/ml 2B5 effectively neutralizes 1 ng/ml PGE 2 (20).…”

Section: Reagentsmentioning

confidence: 99%

Cutting Edge: Cyclooxygenase-2 Activation Suppresses Th1 Polarization in Response toHelicobacter pylori

Meyer¹,

Ramanujam²,

Gobert

et al. 2003

The Journal of Immunology

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Helicobacter pylori infection causes a Th1-driven mucosal immune response. Cyclooxygenase (COX)-2 is up-regulated in lamina propria mononuclear cells in H. pylori gastritis. Because COX-2 can modulate Th1/Th2 balance, we determined whether H. pylori activates COX-2 in human PBMCs, and the effect on cytokine and proliferative responses. There was significant up-regulation of COX-2 mRNA and PGE2 release in response to H. pylori preparations. Addition of COX-2 inhibitors or an anti-PGE2 Ab resulted in a marked increase in H. pylori-stimulated IL-12 and IFN-γ production, and a decrease in IL-10 levels. Addition of PGE2 or cAMP, the second messenger activated by PGE2, had the opposite effect. Similarly, stimulated cell proliferation was increased by COX-2 inhibitors or anti-PGE2 Ab, and was decreased by PGE2. Our findings indicate that COX-2 has an immunosuppressive role in H. pylori gastritis, which may protect the mucosa from severe injury, but may also contribute to the persistence of the infection.

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“…An increase in serum level of IFN-g occurs in H. pylori-infected patients and experimental animal models and is a predictor of clinical outcome (19,20), and IFN-g is also increased in PBMCs infected with H. pylori (21). The pathogenic and antimicrobial roles of IFN-g were identified because mice deficient in IFN-g, T-bet (a transcription factor of IFN-g), or IRF1 (a downstream modulator of IFN-g) fail to develop gastric inflammation but have increased susceptibility to H. pylori colonization (12,(22)(23)(24)(25)(26).…”

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confidence: 99%

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Wang

Chen

Sheu

et al. 2014

The Journal of Immunology

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Helicobacter pylori infection not only induces gastric inflammation but also increases the risk of gastric tumorigenesis. IFN-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ–mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet-unknown mechanism. This study was aimed at investigating the mechanism of H. pylori–induced IFN-γ resistance. Postinfection of viable H. pylori decreased IFN-γ–activated signal transducers and activators of transcription 1 and IFN regulatory factor 1 not only in human gastric epithelial MKN45 and AZ-521 but also in human monocytic U937 cells. H. pylori caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain–containing phosphatase (SHP) 2. Pharmacologically and genetically inhibiting SHP2 reversed H. pylori–induced IFN-γ resistance. In contrast to a clinically isolated H. pylori strain HP238, the cytotoxin-associated gene A (CagA) isogenic mutant strain HP238CagAm failed to induce IFN-γ resistance, indicating that CagA regulates this effect. Notably, HP238 and HP238CagAm differently caused SHP2 phosphorylation; however, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori–induced SHP2 phosphorylation; however, ROS/SHP2 mediated IFN-γ resistance in a CagA-regulated manner. This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori–induced IFN-γ resistance.

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Modulation of Innate Cytokine Responses by Products ofHelicobacter pylori

Cited by 79 publications

References 46 publications

Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes

Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes

Cutting Edge: Cyclooxygenase-2 Activation Suppresses Th1 Polarization in Response toHelicobacter pylori

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

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