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Gastroduodenal section free papers
Classical and alternative pathway nuclear factor-κB signalling differentially regulate gastric epithelial responses to helicobacter felis infection
  1. M D Burkitt *1,
  2. A Varro2,
  3. J H Caamano3,
  4. D M Pritchard1
  1. 1Department of Gastroenterology, The University of Liverpool, Liverpool, UK
  2. 2Department of Cellular and Molecular Physiology, The University of Liverpool, Liverpool, UK
  3. 3Unit of Immune Regulation, The University of Birmingham, Birmingham, UK

Abstract

Introduction Classical pathway NF-κB signalling is implicated in the pathogenesis of several inflammation associated cancers, including colitis associated colon cancer and Helicobacter associated gastric cancer. However, the role of individual NF-κB family members and the function of alternative pathway NF-κB signalling have not previously been assessed in this context. We have therefore investigated whether abrogation of classical and alternative pathway NF-κB signalling altered murine responses to Helicobacter felis infection.

Methods 6-week-old female NF-κB1 null (p50-/-), NF-κB2 null (p52-/-), c-Rel null and C57BL/6 mice were infected with H. felis by oral gavage and culled 6 weeks later. Tissues were processed for histological analysis and immunohistochemistry.

Results H. felis infection of wild-type mice resulted in gastric atrophy (29% fewer parietal cells were observed in infected than in control mice (p < 0.05, 1-way ANOVA and Holm Sidak post hoc test)), a 1.5-fold increase in the number of Ki67 positive proliferating cells and no significant change in the number of active caspase 3 positive apoptotic cells. Animals with abrogated classical pathway NF-κB signalling also developed gastric atrophy after H. felis infection. However, whereas infected c-Rel null animals showed similar parietal cell, proliferation and apoptotic indices to infected wild-type mice, p50-/- animals developed more severe pathology with significantly increased inflammation scores (p < 0.05, Mann–Whitney U) and a more marked 62% reduction in parietal cell number (p < 0.05, 1-way ANOVA). This was associated with significant 2.1-fold and 7.6-fold increases in the number of proliferating and apoptotic cells, respectively (p < 0.05, 2-way ANOVA). By contrast, infected p52-/- mice showed much lower inflammation scores than wild-type mice (p < 0.05, MWU) following H. felis infection and did not develop gastric atrophy, with only 3% parietal cell loss (p < 0.05, 1-way ANOVA). In addition, these mice showed no significant changes in proliferation or apoptosis following infection with H. felis, and demonstrated similar proliferation and apoptotic indices to untreated wild-type mice.

Conclusion NF-κB1 mediated signalling protects the gastric mucosa from Helicobacter induced atrophy, whereas alternative pathway NF-κB signalling is required for the development of both inflammation and atrophy following infection with this organism. This supports the hypothesis that classical and alternative pathway signalling differentially affect long-term outcomes, including carcinogenesis, following H. felis infection in C57BL/6 mice.

  • gastric atrophy
  • H. pylori
  • NF-κB

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Footnotes

  • Competing interests None.

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