15-DEOXY-Δ12,14-PROSTAGLANDIN J2 SUPPRESSES RANTES EXPRESSION BY INHIBITING NADPH OXIDASE ACTIVATION IN HELICOBACTER PYLORI-INFECTED GASTRIC EPITHELIAL CELLS

Peroxisome proliferators-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor. 15 deoxy-(12,14) prostaglandin J(2) (15d-PGJ(2)) is a potent PPAR-gamma ligand and acts as an anti-inflammatory agent via PPAR-gamma-dependent and independent mechanisms. Helicobacter pylori (H. pylori) induces gastric inflammation by inducing the activation of oxidant-sensitive transcription factor NF-kappa B and cytokine expression in gastric epithelial cells. Since 15d-PGJ(2) inhibits NF-kappa B 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 H2O2 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 H2O2 and RANTES in H. pylori-infected cells. H. pylori induced the production of H2O2 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. Conclusion: 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.