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| Subject Categories: Molecular Biology of Disease |
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| The EMBO Journal
(2004) 23, 1669–1678, doi:10.1038/sj.emboj.7600170 Published online 11 March 2004 |
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| Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice |
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| Hiroko Oshima1, Masanobu Oshima1, Kayo Inaba2 and Makoto M Taketo1 |
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1 Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 2 Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan To whom correspondence should be addressed Makoto M Taketo, Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida-Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: +81 75 753 4391; Fax: +81 75 753 4402; E-mail: taketo@mfour.med.kyoto-u.ac.jp Received 1 September 2003; Accepted 23 February 2004; Published online 11 March 2004. |
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| Abstract |
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| Cyclooxygenase-2 (COX-2), the rate-limiting enzyme for prostanoid biosynthesis, plays a key role in gastrointestinal carcinogenesis. Among various prostanoids, prostaglandin E2 (PGE2) appears to be most responsible for cancer development. To investigate the role of PGE2 in gastric tumorigenesis, we constructed transgenic mice simultaneously expressing COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the gastric epithelial cells. The transgenic mice developed metaplasia, hyperplasia and tumorous growths in the glandular stomach with heavy macrophage infiltrations. Although gastric bacterial counts in the transgenic mice were within the normal range, treatment with antibiotics significantly suppressed activation of the macrophages and tumorous hyperplasia. Importantly, the antibiotics treatment did not affect the macrophage accumulation. Notably, treatment of the transgenic mice with lipopolysaccharides induced proinflammatory cytokines through Toll-like receptor 4 in the gastric epithelial cells. These results indicate that an increased level of PGE2 enhances macrophage infiltration, and that they are activated through epithelial cells by the gastric flora, resulting in gastric metaplasia and tumorous growth. Furthermore, Helicobacter infection upregulated epithelial PGE2 production, suggesting that the COX-2/mPGES-1 pathway contributes to the Helicobacter-associated gastric tumorigenesis. |
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| Keywords: COX-2, gastric hyperplasia, Helicobacter, macrophages, mPGES-1 |
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