title: 15-deoxy-D12,14-prostaglandin J2 suppresses RANTES expression by inhibiting NADPH oxidase activation in Helicobacter pylori-infected gastric epithelial cells.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: B
authors.initials: B
authors.lastname: Cha
authors.forename: J W
authors.initials: JW
authors.lastname: Lim
authors.forename: K H
authors.initials: KH
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Kim
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation / Q000502:physiology*; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology; D005753:Gastric Mucosa / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology; D016481:Helicobacter Infections / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy; D016480:Helicobacter pylori; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000502:physiology / Q000627:therapeutic use
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000900:Anti-Bacterial Agents; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019255:NADPH Oxidases; D015230:Prostaglandin D2