Abstract
BackgroundThe association between Helicobacter pylori infection and upper gastrointestinal disease is well established. However, only a small fraction of H. pylori carriers develop disease, and there are great geographical differences in disease penetrance. The explanation to this enigma lies in the interaction between the bacterium and the host. H. pylori Outer Membrane Phospholipase A (OMPLA) has been suggested to play a role in the virulence of this bacterium. The aim of this study was to profile the most significant cellular pathways and biological processes affected in gastric epithelial cells during 24 h of H. pylori exposure, and to study the inflammatory response to OMPLA+ and OMPLA- H. pylori variants.ResultsInterleukin-8 was the most significantly up-regulated gene and appears to play a paramount role in the epithelial cell response to H. pylori infection and in the pathological processes leading to gastric disease. MAPK and NF-kappaB cellular pathways were powerfully activated, but did not seem to explain the impressive IL-8 response. There was marked up-regulation of TP53BP2, whose corresponding protein ASPP2 may interact with H. pylori CagA and cause marked p53 suppression of apoptosis. Other regulators of apoptosis also showed abberant regulation. We also identified up-regulation of several oncogenes and down-regulation of tumor suppressor genes as early as during the first 24 h of infection. H. pylori OMPLA phase variation did not seem to influence the inflammatory epithelial cell gene response in this experiment.ConclusionIn whole genome analysis of the epithelial response to H. pylori exposure, IL-8 demonstrated the most marked up-regulation, and was involved in many of the most important cellular response processes to the infection. There was dysregulation of apoptosis, tumor suppressor genes and oncogenes as early as in the first 24 h of H. pylori infection, which may represent early signs of gastric tumorigenesis. OMPLA+/-did not affect the acute inflammatory response to H. pylori.
Highlights
The association between Helicobacter pylori infection and upper gastrointestinal disease is well established
To study the cellular morphology following H. pylori infection at 3 and 6 h, non-exposed and H. pylori exposed cells were stained and examined with immunofluorescence microscopy (Figure 1). At both 3 and 6 h there was no significant difference in the ability between the Outer Membrane Phospholipase A (OMPLA)+ and OMPLA- H. pylori to adhere to AGS cells, and there were no significant differences in the morphological changes in the AGS cells in response to exposure to the two variants
The cDNA profile of H. pylori exposed AGS cells were compared against non-infected control cells at six separate time points within 24 h. 7498 chip probes corresponding to 6237 human genes showed differential expression in the infected cells compared to control cells at no less than 1 time point (p < 0. 05) (Additional file 1: Table S1)
Summary
The association between Helicobacter pylori infection and upper gastrointestinal disease is well established. Only a small fraction of H. pylori carriers develop disease, and there are great geographical differences in disease penetrance. The explanation to this enigma lies in the interaction between the bacterium and the host. Direct action of H. pylori on epithelial cells may promote carcinogenesis. CagA injection into gastric epithelial cells up-regulates the anti-apoptotic MCL protein [11] and interferes with apoptosis-stimulating protein 2 of p53 (ASPP2) [12]. ASPP2 inhibition causes enhanced degradation of p53, in a way similar to DNA tumor viruses, thereby decreasing apoptotic activity, which may explain the increased risk of GC associated with cagA+ H. pylori infection
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