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.