Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes.

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.

Citation

Hideo Kohka Takahashi, Takeshi Watanabe, Akira Yokoyama, Hiromi Iwagaki, Tadashi Yoshino, Noriaki Tanaka, Masahiro Nishibori. Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes. Molecular pharmacology. 2006 Aug;70(2):450-3

Mesh Tags

Substances

PMID: 16723495

search → result