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.
Highlights
The incidence of inflammatory bowel disease (IBD) is increasing, and current concepts attribute IBD to inappropriate chronic inflammatory responses to commensal microbes in genetically susceptible patients [1]
This study focused on E receptor (EP) 4–associated protein (EPRAP), a novel EP4 receptor–associated protein, implicated in its signaling pathway
EPRAP was localized in stromal macrophages of ulcerative colitis patients
Summary
The incidence of inflammatory bowel disease (IBD) is increasing, and current concepts attribute IBD to inappropriate chronic inflammatory responses to commensal microbes in genetically susceptible patients [1]. Misoprostol, a synthetic PGE1 analog, potently protects human colonic mucosa against mucosal insults [3]. Misoprostol frequently induces severe diarrhea in humans [6], and treatment with EP receptor agonists can induce vasodilatation, causing hypotension [7]. In a phase 2 clinical trial of an EP4-selective agonist for ulcerative colitis patients, diarrhea or hypotension occurred in patients with EP4 agonist treatment [8]. These undesired effects of PGE2 and EP4 agonists likely result from increased cAMP production in colonic or vascular endothelial cells. The need is urgent to develop molecules that stimulate EP4 receptors but have fewer side effects to treat IBD, and potentially other inflammatory diseases
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