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Title: EP4 Receptor–Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis
Authors: Nakatsuji, Masato
Minami, Manabu  kyouindb  KAKEN_id  orcid (unconfirmed)
Seno, Hiroshi  kyouindb  KAKEN_id
Yasui, Mika
Komekado, Hideyuki
Higuchi, Sei
Fujikawa, Risako
Nakanishi, Yuki  kyouindb  KAKEN_id
Fukuda, Akihisa  kyouindb  KAKEN_id
Kawada, Kenji  kyouindb  KAKEN_id
Sakai, Yoshiharu
Kita, Toru
Libby, Peter
Ikeuchi, Hiroki
Yokode, Masayuki  kyouindb  KAKEN_id
Chiba, Tsutomu
Author's alias: 南, 学
妹尾, 浩
福田, 晃久
河田, 健二
坂井, 義治
横出, 正之
千葉, 勉
Issue Date: 6-Oct-2015
Publisher: Public Library of Science
Journal title: PLOS Genetics
Volume: 11
Issue: 10
Thesis number: e1005542
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.
Rights: © 2015 Nakatsuji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
DOI(Published Version): 10.1371/journal.pgen.1005542
PubMed ID: 26439841
Appears in Collections:Journal Articles

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