Regulation of IL-18 in Helicobacter pylori infection.
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.
Yamauchi
Kazuyoshi
K
Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, USA.
Choi
Il-Ju
IJ
Lu
Hong
H
Ogiwara
Hiroaki
H
Graham
David Y
DY
Yamaoka
Yoshio
Y
D000942:Antigens, Bacterial / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005753:Gastric Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017384:Sequence Deletion; D037521:Virulence Factors / Q000378:metabolism*
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D020382:Interleukin-18; D016328:NF-kappa B; C526444:OipA protein, Helicobacter pylori; D012333:RNA, Messenger; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases