Rebamipide inhibits ceramide-induced interleukin-8 production in Kato III human gastric cancer cells

Helicobacter pylori adheres to gastric epithelial cells and stimulates inte rleukin-8 production. Ceramide, a lipid second messenger, has become known as an important mediator of some actions of several cytokines. We have rece ntly reported that H. pylori-dependent ceramide production may activate nuc lear factor-kappaB and mediate interleukin-8 expression in human gastric ca ncer cell lines. In this study, we evaluated the effect of rebamipide, an a ntigastritis and antiulcer agent, on H. pylori-dependent ceramide productio n and subsequent interleukin-8 expression in Kato III cells. Rebamipide inh ibited ceramide-induced interleukin-8 expression in a dose-dependent manner . Rebamipide decreased the ceramide-induced increase of the interleukin-8 m RNA level as assessed by Northern blotting. Rebamipide suppressed interleuk in-8 gene transcription and nuclear factor-kappaB-dependent transcriptional activity as assessed by luciferase assay. Rebamipide inhibited the ceramid e-induced degradation of I kappaB-alpha (a major cytoplasmic inhibitor of n uclear factor-kappaB), further supporting that rebamipide inhibits the acti vation of nuclear factor-kappaB. Rebamipide also inhibited the ceramide-dep endent activation of mitogen-activated protein kinases. Furthermore, rebami pide significantly attenuated the H. pylori-dependent increase in the intra cellular ceramide level. These results suggest a novel mechanism by which r ebamipide may protect against the mucosal inflammation associated with H. p ylori infection.