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Identification of novel cyclooxygenase-2-dependent genes in Helicobacter pylori infection in vivo.

Walduck AK, Weber M, Wunder C, Juettner S, Stolte M, Vieth M, Wiedenmann B, Meyer TF, Naumann M, Hoecker M - Mol. Cancer (2009)

Bottom Line: Under conditions of Cox-2 inhibition, 160 target genes were regulated as a result of H. pylori infection.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.These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany. AWalduck@unimelb.edu.au

ABSTRACT

Background: 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. 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.

Results: Gene 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.

Conclusion: 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. These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity.

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Related in: MedlinePlus

Global gene expression in the gastric mucosa of mice infected with H. pylori. A. Venn diagram illustrating the breakdown of differentially expressed genes (more than 3 fold up or down) over the period of the study. The number of genes passing the cut-off criteria is indicated for each experimental comparison: Infected versus non-infected mice (V vs V+Hp), infected mice versus NS398 treated and infected mice (V+Hp vs NS398+Hp), and non-infected mice versus NS398 treated (V vs NS398). Numbers in parentheses represent the number total genes differently expressed in the three experimental comparisons. B. Trend plots representing global gene expression measured in the 3 experimental comparisons. Each point on the y-axes represents the average expression ratio for genes passing the cut-off criteria at weeks 6, 13 and 19 after treatment starts, i.e. one line represents one gene. The 33 infection-related genes that were differently expressed as a result of NS398 treatment are highlighted in red for all comparisons. Cox-2 (Ptgs2) is indicated by the yellow line.
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Figure 2: Global gene expression in the gastric mucosa of mice infected with H. pylori. A. Venn diagram illustrating the breakdown of differentially expressed genes (more than 3 fold up or down) over the period of the study. The number of genes passing the cut-off criteria is indicated for each experimental comparison: Infected versus non-infected mice (V vs V+Hp), infected mice versus NS398 treated and infected mice (V+Hp vs NS398+Hp), and non-infected mice versus NS398 treated (V vs NS398). Numbers in parentheses represent the number total genes differently expressed in the three experimental comparisons. B. Trend plots representing global gene expression measured in the 3 experimental comparisons. Each point on the y-axes represents the average expression ratio for genes passing the cut-off criteria at weeks 6, 13 and 19 after treatment starts, i.e. one line represents one gene. The 33 infection-related genes that were differently expressed as a result of NS398 treatment are highlighted in red for all comparisons. Cox-2 (Ptgs2) is indicated by the yellow line.

Mentions: RNA from animals with similar scores and colonization levels (3 mice per group) were pooled and used to perform the three experimental comparisons: non-infected versus infected (V vs V+Hp), infected versus NS398 treated and infected (V+Hp vs NS398+Hp), and non-infected versus non-infected and NS398 treated (V vs NS398) (Figure 2A). The experiment was designed to enable us to determine gene expression profiles in the stomachs of mice receiving vehicle alone or NS398 in vehicle, and to isolate these from the effects of H. pylori infection.


Identification of novel cyclooxygenase-2-dependent genes in Helicobacter pylori infection in vivo.

Walduck AK, Weber M, Wunder C, Juettner S, Stolte M, Vieth M, Wiedenmann B, Meyer TF, Naumann M, Hoecker M - Mol. Cancer (2009)

Global gene expression in the gastric mucosa of mice infected with H. pylori. A. Venn diagram illustrating the breakdown of differentially expressed genes (more than 3 fold up or down) over the period of the study. The number of genes passing the cut-off criteria is indicated for each experimental comparison: Infected versus non-infected mice (V vs V+Hp), infected mice versus NS398 treated and infected mice (V+Hp vs NS398+Hp), and non-infected mice versus NS398 treated (V vs NS398). Numbers in parentheses represent the number total genes differently expressed in the three experimental comparisons. B. Trend plots representing global gene expression measured in the 3 experimental comparisons. Each point on the y-axes represents the average expression ratio for genes passing the cut-off criteria at weeks 6, 13 and 19 after treatment starts, i.e. one line represents one gene. The 33 infection-related genes that were differently expressed as a result of NS398 treatment are highlighted in red for all comparisons. Cox-2 (Ptgs2) is indicated by the yellow line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667483&req=5

Figure 2: Global gene expression in the gastric mucosa of mice infected with H. pylori. A. Venn diagram illustrating the breakdown of differentially expressed genes (more than 3 fold up or down) over the period of the study. The number of genes passing the cut-off criteria is indicated for each experimental comparison: Infected versus non-infected mice (V vs V+Hp), infected mice versus NS398 treated and infected mice (V+Hp vs NS398+Hp), and non-infected mice versus NS398 treated (V vs NS398). Numbers in parentheses represent the number total genes differently expressed in the three experimental comparisons. B. Trend plots representing global gene expression measured in the 3 experimental comparisons. Each point on the y-axes represents the average expression ratio for genes passing the cut-off criteria at weeks 6, 13 and 19 after treatment starts, i.e. one line represents one gene. The 33 infection-related genes that were differently expressed as a result of NS398 treatment are highlighted in red for all comparisons. Cox-2 (Ptgs2) is indicated by the yellow line.
Mentions: RNA from animals with similar scores and colonization levels (3 mice per group) were pooled and used to perform the three experimental comparisons: non-infected versus infected (V vs V+Hp), infected versus NS398 treated and infected (V+Hp vs NS398+Hp), and non-infected versus non-infected and NS398 treated (V vs NS398) (Figure 2A). The experiment was designed to enable us to determine gene expression profiles in the stomachs of mice receiving vehicle alone or NS398 in vehicle, and to isolate these from the effects of H. pylori infection.

Bottom Line: Under conditions of Cox-2 inhibition, 160 target genes were regulated as a result of H. pylori infection.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.These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany. AWalduck@unimelb.edu.au

ABSTRACT

Background: 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. 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.

Results: Gene 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.

Conclusion: 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. These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity.

Show MeSH
Related in: MedlinePlus