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.
Takahashi
Hideo Kohka
HK
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Watanabe
Takeshi
T
Yokoyama
Akira
A
Iwagaki
Hiromi
H
Yoshino
Tadashi
T
Tanaka
Noriaki
N
Nishibori
Masahiro
M
D000818:Animals; D002927:Cimetidine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D020382:Interleukin-18 / Q000096:biosynthesis*; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000502:physiology*
D006635:Histamine H2 Antagonists; D020382:Interleukin-18; D011970:Receptors, Histamine H2; D002927:Cimetidine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases