Rebamipide inhibits ceramide-induced interleukin-8 production in Kato III human gastric cancer cells.
Helicobacter pylori adheres to gastric epithelial cells and stimulates interleukin-8 production. Ceramide, a lipid second messenger, has become known as an important mediator of some actions of several cytokines. We have recently reported that H. pylori-dependent ceramide production may activate nuclear factor-kappaB and mediate interleukin-8 expression in human gastric cancer cell lines. In this study, we evaluated the effect of rebamipide, an antigastritis and antiulcer agent, on H. pylori-dependent ceramide production and subsequent interleukin-8 expression in Kato III cells. Rebamipide inhibited ceramide-induced interleukin-8 expression in a dose-dependent manner. Rebamipide decreased the ceramide-induced increase of the interleukin-8 mRNA level as assessed by Northern blotting. Rebamipide suppressed interleukin-8 gene transcription and nuclear factor-kappaB-dependent transcriptional activity as assessed by luciferase assay. Rebamipide inhibited the ceramide-induced degradation of IkappaB-alpha (a major cytoplasmic inhibitor of nuclear factor-kappaB), further supporting that rebamipide inhibits the activation of nuclear factor-kappaB. Rebamipide also inhibited the ceramide-dependent activation of mitogen-activated protein kinases. Furthermore, rebamipide significantly attenuated the H. pylori-dependent increase in the intracellular ceramide level. These results suggest a novel mechanism by which rebamipide may protect against the mucosal inflammation associated with H. pylori infection.
Masamune
A
A
Department of Gastroenterology, Division of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan. amasamune@int3.med.tohoku.ac.jp
Yoshida
M
M
Sakai
Y
Y
Shimosegawa
T
T
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016481:Helicobacter Infections / Q000473:pathology; D016480:Helicobacter pylori; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000096:biosynthesis; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000897:Anti-Ulcer Agents; D002518:Ceramides; D016209:Interleukin-8; D016328:NF-kappa B; D015363:Quinolones; D020928:Mitogen-Activated Protein Kinases; C052785:rebamipide; D000409:Alanine