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* Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030;
Research Institute and Hospital, National Cancer Center, Gyeonggi, Republic of Korea; and
Department of Gastroenterology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
The gastric mucosal immune response is thought to be comprised predominantly of the Th1 type; however, there are limited data regarding the role of IL-18 in Helicobacter pylori-induced inflammation. We investigated IL-18 levels in gastric mucosal biopsy specimens as well as in isolated gastric epithelial cells and lamina propria mononuclear cells. We also investigated IL-18 levels in gastric epithelial cells and the monocyte cell line THP-1 cocultured with H. pylori. In both systems, IL-18 levels were markedly enhanced in H. pylori-infected epithelial cells and monocytes. IL-18 levels in H. pylori-infected gastric mucosa were well correlated with the severity of gastric inflammation, confirming that H. pylori-induced IL-18 plays an important role in gastric injury. Virulence factors of H. pylori; the cag pathogenicity island and OipA affected IL-18 induction in different manners. Up-regulation of IL-18 mRNA/protein in epithelial cells was dependent on both virulence factors. Interestingly, up-regulation of IL-18 mRNA in monocytes was independent of both factors, whereas IL-18 protein was OipA dependent – cag pathogenicity island independent, indicating that OipA regulates IL-18 induction in monocytes at the posttranscriptional level. IL-18 levels in the gastric biopsy specimens showed similar patterns to those in lamina propria mononuclear cells with respect to virulence factors, suggesting that submucosal monocytes/macrophages are the main source of IL-18 induced by H. pylori infection. H. pylori appeared to regulate the ERK/JNK
AP-1 pathway in both cell types. In addition, OipA and its related p38 pathway may be closely involved in IL-18 induction in H. pylori-infected gastric mucosa and may contribute to gastric injury.
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1 This work was supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs and by Public Health Service Grant DK56338, which funds the Texas Gulf Coast Digestive Diseases Center. Y.Y. is supported in part by National Institutes of Health Grant DK 62813.
2 Current address: Department of Laboratory Medicine, Shinshu University Hospital, Nagano, Japan.
3 Address correspondence and reprint requests to Dr. Yoshio Yamaoka, Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, (111D) Room 3A-320, Houston, TX 77030. E-mail address: yyamaoka{at}bcm.tmc.edu
4 Abbreviations used in this paper: PAI, pathogenicity island; LPMC, lamina propria mononuclear cell; DTT, dithiothreitol; MNC, mononuclear cell; PMN, polymorphonuclear leukocyte; MOI, multiplicity of infection.
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