Abstract
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-κB 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-κB-dependent transcriptional activity as assessed by luciferase assay. Rebamipide inhibited the ceramide-induced degradation of IκB-α (a major cytoplasmic inhibitor of nuclear factor-κB), further supporting that rebamipide inhibits the activation of nuclear factor-κB. Rebamipide also inhibited the ceramide-dependent activation of mitogen-activated protein kinases. Furthermore, rebamipide significantly attenuated theH. pylori-dependent increase in the intracellular ceramide level. These results suggest a novel mechanism by which rebamipide may protect against the mucosal inflammation associated withH. pylori infection.
Footnotes
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This study was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture, Japan (to A.M.).
- Abbreviations:
- IL
- interleukin
- NF-κB
- nuclear factor-κB
- AP-1
- activator protein-1
- TNF-α
- tumor necrosis factor-α
- MAP
- mitogen-activated protein
- bp
- base pair
- ERK
- extracellular signal-regulated kinase
- JNK/SAPK
- c-Jun NH2-terminal kinase/stress-activated protein kinase
- Received January 17, 2001.
- Accepted April 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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