RRC ID 42106
Author Oshima H, Oshima M, Inaba K, Taketo MM.
Title Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice.
Journal EMBO J
Abstract 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.
Volume 23(7)
Pages 1669-78
Published 2004-4-7
DOI 10.1038/sj.emboj.7600170
PII 7600170
PMID 15014433
PMC PMC391075
MeSH Animals Anti-Bacterial Agents / pharmacology Anti-Bacterial Agents / therapeutic use Cell Differentiation Cells, Cultured Chemokines / immunology Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors / metabolism Cytokines / immunology Epithelial Cells / cytology Epithelial Cells / enzymology Gastric Mucosa / cytology Gastric Mucosa / drug effects Gastric Mucosa / immunology Gastric Mucosa / microbiology Helicobacter Infections Hyperplasia Intramolecular Oxidoreductases / genetics Intramolecular Oxidoreductases / immunology* Lipopolysaccharides / pharmacology Macrophage Activation / physiology* Macrophages / immunology* Mice Mice, Transgenic Microsomes / enzymology Prostaglandin-E Synthases Prostaglandin-Endoperoxide Synthases / genetics Prostaglandin-Endoperoxide Synthases / immunology* Receptors, Immunologic / genetics Receptors, Immunologic / metabolism Stomach Neoplasms / drug therapy Stomach Neoplasms / immunology* Stomach Neoplasms / pathology* Toll-Like Receptor 4
IF 9.889
Times Cited 189
Human and Animal Cells RAW 264(RCB0535)