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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Atsushi Masamune, Masayoshi Yoshida, Yoshitaka Sakai and Tooru Shimosegawa
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 485-492;
Atsushi Masamune
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Masayoshi Yoshida
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Yoshitaka Sakai
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Tooru Shimosegawa
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Atsushi Masamune, Masayoshi Yoshida, Yoshitaka Sakai and Tooru Shimosegawa
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 485-492;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Atsushi Masamune, Masayoshi Yoshida, Yoshitaka Sakai and Tooru Shimosegawa
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 485-492;
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