TY - JOUR T1 - Cimetidine Induces Interleukin-18 Production through H2-Agonist Activity in Monocytes JF - Molecular Pharmacology JO - Mol Pharmacol SP - 450 LP - 453 DO - 10.1124/mol.106.025890 VL - 70 IS - 2 AU - Hideo Kohka Takahashi AU - Takeshi Watanabe AU - Akira Yokoyama AU - Hiromi Iwagaki AU - Tadashi Yoshino AU - Noriaki Tanaka AU - Masahiro Nishibori Y1 - 2006/08/01 UR - http://molpharm.aspetjournals.org/content/70/2/450.abstract N2 - 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. ER -