Nakatsuji, MasatoMinami, ManabuSeno, HiroshiYasui, MikaKomekado, HideyukiHiguchi, SeiFujikawa, RisakoNakanishi, YukiFukuda, AkihisaKawada, KenjiSakai, YoshiharuKita, ToruLibby, PeterIkeuchi, HirokiYokode, MasayukiChiba, Tsutomu2015-11-032015Nakatsuji, M., M. Minami, H. Seno, M. Yasui, H. Komekado, S. Higuchi, R. Fujikawa, et al. 2015. “EP4 Receptor–Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis.” PLoS Genetics 11 (10): e1005542. doi:10.1371/journal.pgen.1005542. http://dx.doi.org/10.1371/journal.pgen.1005542.1553-7390http://nrs.harvard.edu/urn-3:HUL.InstRepos:23473864Prostaglandin 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.en-USJournal Article2015-11-0310.1371/journal.pgen.1005542