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

Masato Nakatsuji, Manabu Minami, Hiroshi Seno, Mika Yasui, Hideyuki Komekado, Sei Higuchi, Risako Fujikawa, Yuki Nakanishi, Akihisa Fukuda, Kenji Kawada, Yoshiharu Sakai, Toru Kita, Peter Libby, Hiroki Ikeuchi, Masayuki Yokode, Tsutomu Chiba

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere1005542
JournalPLoS genetics
Volume11
Issue number10
DOIs
Publication statusPublished - Jan 1 2015

Fingerprint

Dextran Sulfate
colitis
sodium sulfate
Colitis
dextran
carcinogenesis
Carcinogenesis
macrophages
Macrophages
sodium
sulfate
protein
Proteins
Intestinal Polyps
proteins
Azoxymethane
bone
bone marrow
azoxymethane
polyp

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Nakatsuji, M., Minami, M., Seno, H., Yasui, M., Komekado, H., Higuchi, S., ... Chiba, T. (2015). EP4 Receptor–Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis. PLoS genetics, 11(10), [e1005542]. https://doi.org/10.1371/journal.pgen.1005542

EP4 Receptor–Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis. / 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.

In: PLoS genetics, Vol. 11, No. 10, e1005542, 01.01.2015.

Research output: Contribution to journalArticle

Nakatsuji, M, Minami, M, Seno, H, Yasui, M, Komekado, H, Higuchi, S, Fujikawa, R, Nakanishi, Y, Fukuda, A, Kawada, K, Sakai, Y, Kita, T, Libby, P, Ikeuchi, H, Yokode, M & Chiba, T 2015, 'EP4 Receptor–Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis', PLoS genetics, vol. 11, no. 10, e1005542. https://doi.org/10.1371/journal.pgen.1005542
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. / EP4 Receptor–Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis. In: PLoS genetics. 2015 ; Vol. 11, No. 10.
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