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First published on May 24, 2006; DOI: 10.1124/mol.106.025890

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Received for publication April 21, 2006.
Revised May 23, 2006.
Accepted for publication May 24, 2006.

Cimetidine induces IL-18 production through H2-agonist activity in monocytes

Hideo K Takahashi 1, Takeshi Watanabe 2, Akira Yokoyama 1, Hiromi Iwagaki 1, Tadashi Yoshino 1, Noriaki Tanaka 1, Masahiro Nishibori 1*

1 Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 2 RIKEN Yokohama Institute Yokohama Research Promotion Division, Yokohama

* Address correspondence to: E-mail: mbori{at}md.okayama-u.ac.jp

Abstract

The present study demonstrated possible mechanism for the improvement of gastrointestinal cancer patients' prognosis by a histamine receptor type2 (H2R) antagonist, cimetidine. This agent, but not the H2R antagonists, ranitidine and famotidine, induced the production of an anti-tumor cytokine, interleukin (IL)-18 by human monocytes and dendritic cells (DC). In fact, cimetidine-induced IL-18 production was antagonized by ranitidine and famotidine. Cimetidine induced the activation of caspase-1, which is reported to modify immature-IL-18 to mature/active-IL-18, and the elevation of intracellular cyclic adenosine monophosphate (cAMP), leading to the activation of protein kinase A (PKA). A PKA inhibitior, H89 abolished the IL-18 production induced by cimetidine. Moreover, the effects of cimetidine on IL-18 production were reproduced in peripheral blood mononuclear cells (PBMC) from wild mice, but not in those from H2R knockout mice. In conclusion, cimetidine, a partial agonist for H2R, has a pharmacological profile different from ranitidine and famotidine, possibly contributing to its anti-tumor activity on gastrointestinal cancers.


Key words: Interleukins, Oncogenes




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