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NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein.

ABSTRACT: The Helicobacter pylori immunodominant protein, CagA, is associated with severe gastritis and carcinoma. Injection of CagA into gastric epithelial cells by type IV secretion leads to actin-cytoskeletal rearrangements and cell scattering. CagA has been reported to have no role in the induction of transcription factor NF-kappaB and IL-8, which are crucial determinants for chronic inflammation. Here, we provide several lines of evidence showing that CagA is able to induce IL-8 in a time- and strain-dependent manner. We also show that by exchanging specific cagA genes, high IL-8-inducing H. pylori strains could be converted into low inducing strains and vice versa. Our results suggest that IL-8 release induced by CagA occurs via a Ras-->Raf-->Mek-->Erk-->NF-kappaB signaling pathway in a Shp-2- and c-Met-independent manner. Thus, CagA is a multifunctional protein capable of effecting both actin remodeling and potentiation of chemokine release.

SUBMITTER: Brandt S

PROVIDER: S-EPMC1166591 | biostudies-literature | 2005 Jun

REPOSITORIES: biostudies-literature

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NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein.

Brandt Sabine S Kwok Terry T Hartig Roland R König Wolfgang W Backert Steffen S

Proceedings of the National Academy of Sciences of the United States of America 20050621 26

The Helicobacter pylori immunodominant protein, CagA, is associated with severe gastritis and carcinoma. Injection of CagA into gastric epithelial cells by type IV secretion leads to actin-cytoskeletal rearrangements and cell scattering. CagA has been reported to have no role in the induction of transcription factor NF-kappaB and IL-8, which are crucial determinants for chronic inflammation. Here, we provide several lines of evidence showing that CagA is able to induce IL-8 in a time- and strain ...[more]

PMID: 15972330

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Project description:AimTo investigate Helicobacter pylori (H. pylori) CagA diversity and to evaluate the association between protein polymorphisms and the occurrence of gastric pathologies.MethodsOne hundred and twenty-two clinical isolates of H. pylori cultured from gastric biopsies obtained from Colombian patients with dyspepsia were included as study material. DNA extracted from isolates was used to determine cagA status, amplifying the C-terminal cagA gene region by polymerase chain reaction. One hundred and six strains with a single amplicon were sequenced and results were used to characterize the 3' variable region of the cagA gene. To establish the number and type of tyrosine phosphorylation motifs Glutamine acid-Proline-Isoleucine-Tyrosine-Alanine (EPIYA) bioinformatic analysis using Amino Acid Sequence Analyzer-Amino Acid Sequence Analyzer software was conducted. Analysis of the association between the number of EPIYA motifs and the gastric pathology was performed using chi(2) test and analysis of the presence of EPIYA-C motifs in relation to the pathology was made by logistic regression odds ratios. Comparisons among EPIYA types found and those reported in GenBank were performed using a proportion test in Statistix Analytical Software version 8.0.ResultsAfter amplification of the 3' of the cagA gene, 106 from 122 isolates presented a single amplicon and 16 showed multiple amplicons. As expected, diversity in the size of the cagA unique fragments among isolates was observed. The 106 strains that presented a single amplicon after 3' cagA amplification came from patients with gastritis (19 patients), atrophic gastritis (21), intestinal metaplasia (26), duodenal ulcer (22) and gastric cancer. DNA sequence analysis showed that the differences in size of 3' cagA unique fragments was attributable to the number of EPIYA motifs: 1.9% had two EPIYA motifs, 62.3% had three, 33.0% had four and 2.8% had five motifs. The majority of tested clinical strains (62.3%) were found to harbor the ABC combination of EPIYA motifs and a significant statistical difference was observed between the frequencies of ABCC tyrosine phosphorylation motifs and Western strains sequences deposited in GenBank.ConclusionThe present report describes a lack of association between H. pylori CagA-protein polymorphisms and pathogenesis. ABCC high frequency variations compared with Western-strains sequences deposited in GenBank require more investigation.

Project description:BACKGROUND: Most of what is known about the Helicobacter pylori (H. pylori) cytotoxin, CagA, pertains to a much-vaunted role as a determinant of gastric inflammation and cancer. Little attention has been devoted to potential roles of CagA in the majority of H. pylori infected individuals not showing oncogenic progression, particularly in relation to host tolerance. Regenerating islet-derived (REG)3? encodes a secreted C-type lectin that exerts direct bactericidal activity against Gram-positive bacteria in the intestine. Here, we extend this paradigm of lectin-mediated innate immunity, showing that REG3? expression is triggered by CagA in the H. pylori-infected stomach. METHODOLOGY/PRINCIPAL FINDINGS: In human gastric mucosal tissues, REG3? expression was significantly increased in CagA-positive, compared to CagA-negative H. pylori infected individuals. Using transfected CagA-inducible gastric MKN28 cells, we recapitulated REG3? induction in vitro, also showing that tyrosine phosphorylated, not unphosphorylated CagA triggers REG3? transcription. In concert with induced REG3?, pro-inflammatory signalling downstream of the gp130 cytokine co-receptor via the signal transducer and activator of transcription (STAT)3 and transcription of two cognate ligands, interleukin(IL)-11 and IL-6, were significantly increased. Exogenous IL-11, but not IL-6, directly stimulated STAT3 activation and REG3? transcription. STAT3 siRNA knockdown or IL-11 receptor blockade respectively abrogated or subdued CagA-dependent REG3? mRNA induction, thus demonstrating a requirement for uncompromised signalling via the IL-11/STAT3 pathway. Inhibition of the gp130-related SHP2-(Ras)-ERK pathway did not affect CagA-dependent REG3? induction, but strengthened STAT3 activation as well as augmenting transcription of mucosal innate immune regulators, IL-6, IL-8 and interferon-response factor (IRF)1. CONCLUSIONS/SIGNIFICANCE: Our results support a model of CagA-directed REG3? expression in gastric epithelial cells via activation of the IL-11/gp130/STAT3 pathway. This response might allow Gram-negative H. pylori to manipulate host immunity to favour its own survival, by reducing the fitness of co-habiting Gram-positive bacteria with which it competes for resources in the gastric mucosal niche.

Dataset Information

NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein.

Publications

NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein.

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