Vol. 298, Issue 2, 485-492, August 2001

Rebamipide Inhibits Ceramide-Induced Interleukin-8 Production in Kato III Human Gastric Cancer Cells

Atsushi Masamune, Masayoshi Yoshida, Yoshitaka Sakai and Tooru Shimosegawa

Department of Gastroenterology, Division of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan

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-B 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-B-dependent transcriptional activity as assessed by luciferase assay. Rebamipide inhibited the ceramide-induced degradation of IB- (a major cytoplasmic inhibitor of nuclear factor-B), further supporting that rebamipide inhibits the activation of nuclear factor-B. 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.