EP4 Receptor-Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis

• Published in: PLoS genetics 2015-10, Vol.11 (10), p.e1005542
• Main Authors: Nakatsuji, Masato, Minami, Manabu, Seno, Hiroshi, Yasui, Mika, Komekado, Hideyuki, Higuchi, Sei, Fujikawa, Risako, Nakanishi, Yuki, Fukuda, Akihisa, Kawada, Kenji, Sakai, Yoshiharu, Kita, Toru, Libby, Peter, Ikeuchi, Hiroki, Yokode, Masayuki, Chiba, Tsutomu
• Format: Article
• Language: English
• Subjects: Animals; Bone marrow; Cancer; Carcinogenesis - genetics; Care and treatment; Colitis, Ulcerative - complications; Colitis, Ulcerative - genetics; Colitis, Ulcerative - pathology; Colonic Neoplasms - complications; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Dextran; Dinoprostone - genetics; Disease Models, Animal; Genetic aspects; Hepatitis; Homeostasis; Humans; Inflammation; Inflammation - genetics; Inflammation - pathology; Inflammatory bowel disease; Inflammatory Bowel Diseases - complications; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - pathology; Macrophages; Macrophages - pathology; Medical research; Mice; Mortality; Physiological aspects; Proteins; Receptors, Prostaglandin E, EP4 Subtype - biosynthesis; Receptors, Prostaglandin E, EP4 Subtype - genetics; Rodents; Science; Tumorigenesis; Ulcerative colitis
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005542

Prostaglandin E2 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.