title: EP4 Receptor-Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakatsuji
authors.affiliation: Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Minami
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Seno
authors.affiliation: Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Yasui
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Komekado
authors.affiliation: Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Higuchi
authors.affiliation: Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Risako
authors.initials: R
authors.lastname: Fujikawa
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Fukuda
authors.affiliation: Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawada
authors.affiliation: Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Kobe City Municipal Center General Hospital, Kobe, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ikeuchi
authors.affiliation: Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokode
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003110:Colonic Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015232:Dinoprostone / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone