prostaglandin-d2 and Helicobacter-Infections

Peroxisome proliferators-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor. 15 deoxy-(12,14) prostaglandin J(2) (15d-PGJ(2)) is a potent PPAR-γ ligand and acts as an anti-inflammatory agent via PPAR-γ-dependent and independent mechanisms. Helicobacter pylori (H. pylori) induces gastric inflammation by inducing the activation of oxidant-sensitive transcription factor NF-κB and cytokine expression in gastric epithelial cells. Since 15d-PGJ(2) inhibits NF-κB activation in various cells, it may suppress H. pylori-induced inflammatory signaling and cytokine expression in gastric epithelial cells. The present study aims to determined the effect of 15d-PGJ(2) on the activation of inflammatory mediators Jak/Stat (Janus kinase/signal transducers and activators of transcription) and induction of cytokine RANTES in H. pylori-infected gastric epithelial AGS cells. Since NADPH oxidase is a candidate for the production of reactive oxygen species in H. pylori-infected gastric epithelial cells, we determined the effect of 15d-PGJ(2) on the activation of NADPH oxdase. AGS cells were cultured in the presence of H. pylori treated with or without 15d-PGJ(2). The activations of NADPH oxidase and Jak1/Stat3, the levels of H(2)O(2) and RANTES in the medium, and DNA binding activity of Stat3 were assessed. A Jak/Stat3 specific inhibitor AG490 and an inhibitor of NADPH oxidase diphenyleneiodonium (DPI) were treated to determine the direct involvement of Jak/Stat and NADPH oxidase on the production of H(2)O(2) and RANTES in H. pylori-infected cells. H. pylori induced the production of H(2)O(2) and RANTES as well as the activations of NADPH oxidase and Jak1/Stat3, which were inhibited by the treatment of 15d-PGJ(2). DPI suppressed H. pylori-induced alterations similar to 15d-PGJ(2). However, AG490 had no effect on NADPH oxidase activation, but reduced the level of RANTES in the medium released from H. pylori-infected cells.. NADPH oxidase activation is an upstream signaling of Jak1/Stat3 activation and induction of RANTES in H. pylori-infected AGS cells. 15d-PGJ(2), inhibits the activations of NADPH oxidase and Jak1/Stat3 and RANTES expression, suggesting that 15d-PGJ(2) may be beneficial for the treatment of H. pylori-induced gastric inflammation.

Topics: Anti-Bacterial Agents; Cell Line, Tumor; Chemokine CCL5; Down-Regulation; Epithelial Cells; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; NADPH Oxidases; Prostaglandin D2

Immunological responses in the host can result in different disease outcomes of Helicobacter pylori-induced gastritis. Prostaglandin E2 derived from cyclooxygenase (COX) and prostaglandin E synthase contribute to gastric protection. Recently, prostaglandin D2 was shown to be involved in host immunity by chemotactic activity through chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), but its role in H. pylori-induced gastritis has not been clarified. We determined the expression levels of mRNAs for haematopoietic PGD synthase (H-PGDS) and lipocalin-type PGDS (L-PGDS), MIP-1 alpha, IFN-gamma, IL-4, and CDX2 in H. pylori-induced gastritis mucosa by quantitative RT-PCR. We found that L-PGDS was constitutively expressed in the epithelium of the glandular base. L-PGDS, but not H-PGDS, was induced on fibroblasts close to infiltrating cells in the H. pylori-infected gastric mucosa. These fibroblasts co-expressed COX-2. The level of L-PGDS mRNA expression decreased as gastritis became more severe. In most of the H. pylori-infected gastric mucosa, CCR5(+) cells had more actively infiltrated than had CRTH2(+) cells. However, the expression level of IFN-gamma was lower in the mucosa of the CRTH2(+) cells-dominantly infiltrating group than that of the less CRTH2-infiltrating group. Exogenously added PGD2 decreased the H. pylori-induced expression of IFN-gamma in peripheral blood mononuclear cells in vitro. The data suggest that PGD2 derived from the gastric mucosa and fibroblasts plays protective roles against inflammatory changes in H. pylori-induced gastritis.

Topics: Adult; Aged; Aged, 80 and over; CDX2 Transcription Factor; Cells, Cultured; Chemokine CCL3; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Female; Gastric Mucosa; Gastritis; Gene Expression Regulation; Helicobacter Infections; Homeodomain Proteins; Humans; Interferon-gamma; Intramolecular Oxidoreductases; Lipocalins; Male; Middle Aged; Prostaglandin D2; Receptors, CCR5; Receptors, Immunologic; Receptors, Prostaglandin; Reverse Transcriptase Polymerase Chain Reaction; Young Adult