Abstract
BackgroundHelicobacter pylori is a crucial determining factor in the pathogenesis of benign and neoplastic gastric diseases. Cyclooxygenase-2 (Cox-2) is the inducible key enzyme of arachidonic acid metabolism and is a central mediator in inflammation and cancer. Expression of the Cox-2 gene is up-regulated in the gastric mucosa during H. pylori infection but the pathobiological consequences of this enhanced Cox-2 expression are not yet characterized. The aim of this study was to identify novel genes down-stream of Cox-2 in an in vivo model, thereby identifying potential targets for the study of the role of Cox- 2 in H. pylori pathogenesis and the initiation of pre- cancerous changes.ResultsGene expression profiles in the gastric mucosa of mice treated with a specific Cox-2 inhibitor (NS398) or vehicle were analysed at different time points (6, 13 and 19 wk) after H. pylori infection. H. pylori infection affected the expression of 385 genes over the experimental period, including regulators of gastric physiology, proliferation, apoptosis and mucosal defence. Under conditions of Cox-2 inhibition, 160 target genes were regulated as a result of H. pylori infection. The Cox-2 dependent subset included those influencing gastric physiology (Gastrin, Galr1), epithelial barrier function (Tjp1, connexin45, Aqp5), inflammation (Icam1), apoptosis (Clu) and proliferation (Gdf3, Igf2). Treatment with NS398 alone caused differential expression of 140 genes, 97 of which were unique, indicating that these genes are regulated under conditions of basal Cox-2 expression.ConclusionThis study has identified a panel of novel Cox-2 dependent genes influenced under both normal and the inflammatory conditions induced by H. pylori infection. These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity.
Highlights
Helicobacter pylori is a crucial determining factor in the pathogenesis of benign and neoplastic gastric diseases
This study has identified a panel of novel Cox-2 dependent genes influenced under both normal and the inflammatory conditions induced by H. pylori infection
Determination of Cox-2 inhibitor concentration To determine the appropriate concentration of inhibitor in our H. pylori infection model, PGE2 levels were measured in the gastric mucosa after H. pylori infection in the presence or absence of Cox-2 inhibition with NS398
Summary
Helicobacter pylori is a crucial determining factor in the pathogenesis of benign and neoplastic gastric diseases. Cyclooxygenase-2 (Cox-2) is the inducible key enzyme of arachidonic acid metabolism and is a central mediator in inflammation and cancer. Expression of the Cox-2 gene is up-regulated in the gastric mucosa during H. pylori infection but the pathobiological consequences of this enhanced Cox-2 expression are not yet characterized. Bacterial colonization of the gastric mucosa leads to development of a chronic inflammatory infiltrate, which is accompanied by enhanced release of inflammatory mediators, growth factors and reactive oxygen metabolites [2,4]. The end products of their enzymatic activity comprise a panel of prostaglandins and thromboxanes, which have been identified as critical regulators of fundamental physiological and pathological processes including platelet aggregation, parturition, T-cell development, inflammation and cancer [57]. Cox-2 enzymatic activity is largely regulated through de novo synthesis of Cox-2 protein [5,6]
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