RvE1, a lipid mediator derived from Eimsapentaenoic add regulates intestinal inflammation in experimental colitis

Backgland /目标;鱼油中富含的Omega-3多不饱和脂肪酸（PUFA），如二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），被认为对包括炎症性肠病（IBD）在内的多种人类炎症性疾病有益，但其分子机制尚不清楚。最近，由EPA诱导的内源性脂质介质Resolvin E1 （RvE1）在局部炎症愈合阶段由环氧化酶-2和5-脂氧合酶等酶产生。有报道称，RvE1在体内可抑制刚地弓形虫可溶性速殖子抗原提取液刺激后脾脏树突状细胞的迁移和体外1L-12的产生。此外，我们报道了RvE1在已知的th1显性急性结肠炎模型小鼠中对tnbs诱导的结肠炎有保护作用。然而，究竟是哪些免疫细胞表达了RvE1受体（ChemR23），这一最近被详细发现的受体及其调控结肠炎症的机制还有待观察。方法/结果;利用单克隆抗体对小鼠表达ChemR23的细胞进行了研究。ChemR23主要在小鼠腹腔巨噬细胞中表达。因此，我们先用RvE1预处理巨噬细胞，再用LPS刺激，然后用实时RT-PCR分析促炎细胞因子mRNA的表达。RvE1治疗导致IL-12p40、TNF-a、IL-10、TGF-β的抑制。接下来，由于已知NFKb在细胞因子调节中起作用，我们评估了刺激后用RvE1预处理是否可以抑制NFKb的核易位。为此，用ChemR23转染的HEK 293细胞或用RvEl或对照预处理的模拟细胞用TNF-α刺激，然后用抗nf - kbp65抗体染色。RvE1预处理通过依赖ChemR23抑制TNF-α-诱导的NF-kB核易位。这些结果表明，RvE1可以调节表达ChemR23的巨噬细胞的免疫应答。因此，我们研究了RvE1在葡聚糖硫酸钠（DSS）诱导的不依赖于T细胞和B细胞的结肠炎中的有益作用。给药3.5%DSS可诱导8周龄C57BL16或ragl缺陷雌性小鼠严重结肠炎。然而，RvE1治疗对DSS结肠炎的临床表现和组织学评分有保护作用。结论：这些数据表明RvE1对th1显性疾病有效，但也抑制巨噬细胞诱导的炎症。因此，这些数据提示RvE1可能是治疗包括人类炎症性肠病在内的多种慢性炎症性疾病的新方法之一。少

Backgland/Aims; Omega-3 polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are enriched in fish oils, are held to be beneficial in a wide range of human inflammatory disorders, including inflammatory bowel disease (IBD), but the molecular mechanism was unknown. Recently, Resolvin E1 (RvE1), an endogenous lipid mediator induced from EPA was identified when generated in local inflammation at the healing stage by the enzymes such as cycloocygenase-2 and 5-lipoxygenase. It was reported that RvE1 inhibited the migration of dendritic cells in the spleen in vivo and the production of 1L-12 in vitro after the stimulation with the pathogen extracts derived from Toxoplasma gondii soluble tachyzoite antigen. In addition, we have reported that RvE1 protected against TNBS-induced colitis in mice which was known to Th1-dominant acute colitis model. However it remains to be seen which immune cells expressed RvE1 receptor (ChemR23) which was re … More cently identified in detail and the mechanism to regulate the colonic inflammation. Methods/Results; The cells expressing ChemR23 in mice was investigated using the monoclonal antibody. ChemR23 expressed mostly in mouse intraperitoneal macrophage. Therefore, intraperitoneal macrophages were pretreated with RvE1, followed by stimulation with LPS and then, mRNA of the proinflammatory cytokines were analyzed by real time RT-PCR. The treatment with RvE1 led to the inhibition of IL-12p40, TNF-a, additionally IL-10, TGF-β. Next, since it is known that NFKb plays a role in cytokine regulation, we assessed whether nuclear translocation of NFKb could be inhibited by the pretreatment with RvE1 after the stimulation. To do so, HEK 293 transfectant cells with ChemR23 or mock cells which were pretreated with RvEl or control were stimulated with TNF-α and then, stained with anti-NF-kBp65 antibody. RvE1 pretreatment inhibits TNF-α-induced nuclear translocation of NF-kB by the dependent manner of ChemR23. These results suggested that RvE1 could regulate immune response on macrophage expressing ChemR23. Therefore, we investigated the beneficial effect of RvE1 in dextran sulfate sodium (DSS) induced colitis which was independent with T cells and B cells. The administration of 3.5%DSS in 8weeks-old C57BL16 or Ragl-deficient female mice was induced severe colitis. RvE1 treatment, however, led to protect DSS colitis about clinical findings and histological score. Conclusion: These data suggest that RvE1 was effective for Th1-dominant disease, but also the suppression of macrophage induced inflammation. Therefore these data suggested that RvE1 may be one of new treatment of many kinds of chronic inflammatory disease including human inflammatory bowel disease. Less