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

0026-895X/06/7002-450-453$20.00
Mol Pharmacol 70:450-453, 2006

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Accelerated Communication

Cimetidine Induces Interleukin-18 Production through H2-Agonist Activity in Monocytes

Hideo Kohka Takahashi, Takeshi Watanabe, Akira Yokoyama, Hiromi Iwagaki, Tadashi Yoshino, Noriaki Tanaka, and Masahiro Nishibori

Departments of Pharmacology (H.K.T., A.Y., M.N.), Gastroenterological Surgery, Transplant, and Surgical Oncology (H.I., N.T.), and Pathology (T.Y.), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; and RIKEN Yokohama Institute Yokohama Research Promotion Division, Yokohama, Kanagawa, Japan (T.W.)

The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients' prognosis by the histamine receptor type 2 (H2R) antagonist cimetidine. This agent, but not the H2R antagonists ranitidine and famotidine, induced the production of an antitumor cytokine, interleukin (IL)-18, by human monocytes and dendritic cells (DC). In fact, ranitidine and famotidine antagonized cimetidine-induced IL-18 production. 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 cAMP, leading to the activation of protein kinase A (PKA). The PKA inhibitor 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 from wild-type 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 antitumor activity on gastrointestinal cancers.

Received April 20, 2006; accepted May 24, 2006

Address correspondence to: Dr. Masahiro Nishibori, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: mbori{at}md.okayama-u.ac.jp






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