Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1β upregulation
Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1β upregulation
复制标题
瑞巴派特基于 IL-1β 上调诱导树突状细胞募集至暴露于 N-甲基-N-硝基-N-亚硝基胍 (MNNG) 的大鼠胃粘膜
DOI：
10.1016/j.bbrc.2012.06.087
复制
发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Yamamichi N
中科院分区：
文献类型：
--
作者：
Goto O;Kambe H;Niimi K;Mochizuki S;Asada-Hirayama I;Minatsuki C;Ono S;Kodashima S;Yamamichi N;Yamaji Y et al;Yamamichi N
瑞巴派特通常用于粘膜保护、胃溃疡愈合、胃炎治疗等，但其对胃恶性肿瘤的作用尚未阐明。使用经口给予N-甲基-N′-硝基-N-亚硝基胍（MNNG）处理的刘易斯和布法罗大鼠品系，我们评价了瑞巴派特对肿瘤抑制性树突状细胞诱导的作用，已知肿瘤抑制性树突状细胞是骨髓来源的异质性抗原呈递细胞，对初始T细胞应答的启动至关重要。使用CD 68作为树突状细胞的标记物，在存在或不存在瑞巴派特和MNNG的情况下，对刘易斯和布法罗大鼠的胃幽门粘膜进行化学分析。瑞巴派特单独治疗14天后，在任一大鼠品系中均未检测到CD 68表达细胞数量的显著变化。然而，在同时暴露于MNNG 14天后，瑞巴派特治疗略微增加了刘易斯品系中的CD 68阳性细胞，并显著增加了布法罗品系中的CD 68阳性细胞。对胃癌细胞中树突状细胞的两种趋化因子IL-1β和TNF-α的分析表明，瑞巴派特以剂量依赖方式诱导IL-1β的表达，而不是TNF-α的表达。使用胃SH-10-TC细胞的荧光素酶启动子测定表明，在IL-1β基因启动子区存在介导瑞巴派特作用的元件。总之，瑞巴派特通过募集树突状细胞（基于胃上皮细胞中IL-1β基因的上调）对胃肿瘤发生具有潜在的肿瘤抑制作用。
Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1β and TNF-α, in the gastric cancer cells showed that expression of IL-1β, but not TNF-α, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1β gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1β gene in gastric epithelial cells.