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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)450-453
Number of pages4
JournalMolecular Pharmacology
Volume70
Issue number2
DOIs
Publication statusPublished - 2006

Fingerprint

Histamine Agonists
Interleukin-18
Cimetidine
Monocytes
Famotidine
Ranitidine
Gastrointestinal Neoplasms
Cyclic AMP-Dependent Protein Kinases
Histamine Receptors
Caspase 1
Protein Kinase Inhibitors
Knockout Mice
Dendritic Cells
Blood Cells
Pharmacology
Cytokines

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes. / Takahashi, Hideo Kohka; Watanabe, Takeshi; Yokoyama, Akira; Iwagaki, Hiromi; Yoshino, Tadashi; Tanaka, Noriaki; Nishibori, Masahiro.

In: Molecular Pharmacology, Vol. 70, No. 2, 2006, p. 450-453.

Research output: Contribution to journalArticle

Takahashi, Hideo Kohka ; Watanabe, Takeshi ; Yokoyama, Akira ; Iwagaki, Hiromi ; Yoshino, Tadashi ; Tanaka, Noriaki ; Nishibori, Masahiro. / Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes. In: Molecular Pharmacology. 2006 ; Vol. 70, No. 2. pp. 450-453.
@article{613f34f1a012473aa3e7f9dc9c07e632,
title = "Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes",
abstract = "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.",
author = "Takahashi, {Hideo Kohka} and Takeshi Watanabe and Akira Yokoyama and Hiromi Iwagaki and Tadashi Yoshino and Noriaki Tanaka and Masahiro Nishibori",
year = "2006",
doi = "10.1124/mol.106.025890",
language = "English",
volume = "70",
pages = "450--453",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes

AU - Takahashi, Hideo Kohka

AU - Watanabe, Takeshi

AU - Yokoyama, Akira

AU - Iwagaki, Hiromi

AU - Yoshino, Tadashi

AU - Tanaka, Noriaki

AU - Nishibori, Masahiro

PY - 2006

Y1 - 2006

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33746265828&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746265828&partnerID=8YFLogxK

U2 - 10.1124/mol.106.025890

DO - 10.1124/mol.106.025890

M3 - Article

VL - 70

SP - 450

EP - 453

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -