title: Monocyte chemoattractant protein-1 is generated via TGF-beta by myofibroblasts in gastric intestinal metaplasia and carcinoma without H. pylori infection.
abstract: Helicobacter pylori (H. pylori) stimulates secretion of monocyte chemoattractant protein 1 (MCP-1) from gastric mucosa. Monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration are recognized in human gastric carcinoma. We have previously generated Cdx2-transgenic mice as model mice for intestinal metaplasia. Both chronic H. pylori-associated gastritis and Cdx2-transgenic mouse stomach develop intestinal metaplasia and finally gastric carcinoma. In this study we have directed our attention to MCP-1 expression in the intestinal metaplastic mucosa and the gastric carcinoma of Cdx2-transgenic mouse stomach. Quantitative real-time PCR was performed to determine MCP-1 and transforming growth factor-beta1 (TGF-beta1) mRNA expression levels and single- or double-label immunohistochemistry was used to evaluate the localization of MCP-1, TGF-beta type I receptor, and alpha-smooth muscle actin (alphaSMA). We determined that MCP-1 mRNA dramatically increased in the intestinal metaplastic mucosa and the gastric carcinoma of Cdx2-transgenic mouse stomach, compared with normal mouse stomach. Both MCP-1 and TGF-beta type I receptor were co-expressed in the alphaSMA-positive myofibroblasts of intestinal metaplastic mucosa and gastric carcinoma. Exogenous application of TGF-beta1 increased MCP-1 mRNA expression levels in the intestinal metaplastic tissue. Furthermore, TGF-beta1 was overexpressed and macrophage was strongly infiltrated in the gastric carcinoma. In conclusion, MCP-1 expression, which was stimulated by TGF-beta1, was recognized in the TGF-beta type I receptor-expressing myofibroblasts of the intestinal metaplastic mucosa and the gastric carcinoma of Cdx2-transgenic mouse stomach. The present results suggest that intestinal metaplasia and gastric carcinoma themselves induce MCP-1 expression independently of H. pylori infection.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Jichi Medical University, Shimotsuke, Tochigi, Japan. muto@jichi.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mutoh
authors.forename: Miho
authors.initials: M
authors.lastname: Sashikawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sugano
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D000071616:CDX2 Transcription Factor; D018932:Chemokine CCL2 / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005753:Gastric Mucosa / Q000473:pathology*; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori; D018398:Homeodomain Proteins / Q000502:physiology; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology; D008297:Male; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D013274:Stomach Neoplasms / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D000199:Actins; D000071616:CDX2 Transcription Factor; C491768:Ccl2 protein, mouse; C487514:Cdx2 protein, mouse; D018932:Chemokine CCL2; D018398:Homeodomain Proteins; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I