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
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
PLoS Genet. 2015 Oct 6;11(10):e1005542. doi: 10.1371/journal.pgen.1005542. eCollection 2015 Oct.
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.
前列腺素E2在维持结肠内环境稳定中发挥着重要作用。最近鉴定出的前列腺素E受体（EP）4相关蛋白（EPRAP）对于体外巨噬细胞中EP4信号的抗炎功能至关重要。为了研究EPRAP在体内的作用，我们检测了EPRAP对结肠炎和结肠炎相关肿瘤发生的影响。在小鼠中，EPRAP缺陷加剧了葡聚糖硫酸钠（DSS）处理诱导的结肠炎。移植EPRAP缺陷骨髓的野生型（WT）或EPRAP缺陷受体比接受WT骨髓的WT或EPRAP缺陷受体发生更严重的DSS诱导的结肠炎。在结肠炎相关肿瘤发生的背景下，全身EPRAP无效突变和骨髓中EPRAP缺陷均增强了由氧化偶氮甲烷（AOM）/DSS处理诱导的肠息肉形成。给予EP4选择性激动剂ONO-AE1-329可改善WT小鼠中DSS诱导的结肠炎，但对EPRAP缺陷小鼠无效。EPRAP缺陷增加了p105、MEK和ERK磷酸化形式的水平，导致DSS诱导的结肠炎中基质巨噬细胞活化。与WT小鼠相比，DSS处理的EPRAP缺陷小鼠的巨噬细胞促炎基因表达明显增加。相比之下，在巨噬细胞中强制表达EPRAP可改善DSS诱导的结肠炎和AOM/DSS诱导的肠息肉形成。这些数据表明，巨噬细胞中的EPRAP在抑制结肠炎症中起关键作用。一致地，EPRAP阳性巨噬细胞也在溃疡性结肠炎患者的结肠基质中积聚。因此，EPRAP可能是炎症性肠病及相关肠道肿瘤发生的潜在治疗靶点。
