期刊
PLoS Genetics
卷 11, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1005542
关键词
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资金
- Japan Society for the Promotion of Science KAKENHI [20890111, 23590361, 23590937, 25112707, 26293173, 24590914, 25461021, 24229005, 24659363, 25130706]
- Research Program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Health and Labour Sciences Research Grants for Research on Intractable Diseases, Hepatitis
- Ministry of Health, Labour and Welfare of Japan
- Suzuken Memorial Foundation
- Metabolic Syndrome Research Forum Fund
- Takeda Science Foundation
- Kobayashi Foundation for Cancer Research
- Naito Foundation
- Princess Takamatsu Cancer Research Fund, Japan [13-24514]
- National Heart, Lung and Blood Institute [RO1 HL080472, PO1 HL048743]
- Grants-in-Aid for Scientific Research [25112707, 24590914, 23590361, 25461021] Funding Source: KAKEN
Prostaglandin E-2 plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4-associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP-deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis.
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