Oligosaccharides from agar inhibit murine intestinal inflammation through the induction of heme oxygenase-1 expression
Oligosaccharides from agar inhibit murine intestinal inflammation through the induction of heme oxygenase-1 expression
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DOI：
10.1007/s00535-012-0719-4
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发表时间：
2013-08-01
影响因子：
6.3
通讯作者：
Yoshikawa, Toshikazu
中科院分区：
文献类型：
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作者：
Higashimura, Yasuki;Naito, Yuji;Yoshikawa, Toshikazu
琼脂糖容易水解产生寡糖，称为琼脂寡糖（agaro-oligosaccharides，AGO）。最近，研究表明AGO诱导巨噬细胞中血红素氧合酶-1（HO-1）的表达，并可能导致抗炎特性。然而，AGO介导的HO-1诱导的分子机制仍然未知，AGO在体内引起抗炎活性的能力也是如此。本研究采用2，4，6-三硝基苯磺酸（TNBS）诱导小鼠结肠炎模型，探讨AGO诱导HO-1表达的机制及其对肠道炎症的治疗作用。比较了接受AGO的小鼠和对照小鼠的粘膜损伤的各自程度。我们使用Western印迹、实时定量PCR（qRT-PCR）和免疫组织化学研究HO-1的表达。采用qRT-PCR和酶联免疫吸附试验检测结肠黏膜中肿瘤坏死因子-α（TNF-α）的表达。诱导主要在F4/80阳性巨噬细胞中观察到。TNBS治疗后结肠损伤和髓过氧化物酶活性的增加被AGO给药抑制。TNBS处理诱导TNF-α表达，AGO给药抑制诱导。然而，HO抑制剂取消AGO介导的结肠炎改善。在RAW 264细胞中，AGO呈时间依赖性和浓度依赖性地增强HO-1表达，并抑制脂多糖诱导的TNF-α表达。此外，琼脂四糖介导的HO-1诱导需要NF-E2相关因子2的功能和c-jun N-末端激酶的磷酸化。我们推断，AGO给药通过诱导巨噬细胞中的HO-1抑制TNBS诱导的小鼠结肠炎。因此，口服AGO可能是炎症性肠病的重要治疗策略。
Agarose is hydrolyzed easily to yield oligosaccharides, designated as agaro-oligosaccharides (AGOs). Recently, it has been demonstrated that AGOs induce heme oxygenase-1 (HO-1) expression in macrophages and that they might lead to anti-inflammatory property. Nevertheless, the molecular mechanism of AGO-mediated HO-1 induction remains unknown, as does AGOs' ability to elicit anti-inflammatory activity in vivo. This study was undertaken to uncover the mechanism of AGO-mediated HO-1 induction and to investigate the therapeutic effect of AGOs on intestinal inflammation.Mice were treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. The respective degrees of mucosal injury of mice that had received AGO and control mice were compared. We investigated HO-1 expression using Western blotting, quantitative real-time PCR (qRT-PCR), and immunohistochemistry. The expression of tumor necrosis factor-alpha (TNF-alpha) was measured using qRT-PCR and enzyme-linked immunosorbent assay.AGO administration induced HO-1 expression in colonic mucosa. The induction was observed mainly in F4/80 positive macrophages. Increased colonic damage and myeloperoxidase activity after TNBS treatment were inhibited by AGO administration. TNBS treatment induced TNF-alpha expression, and AGO administration suppressed induction. However, HO inhibitor canceled AGO-mediated amelioration of colitis. In RAW264 cells, AGOs enhanced HO-1 expression time-dependently and concentration-dependently and suppressed lipopolysaccharide-induced TNF-alpha expression. Furthermore, agarotetraose-mediated HO-1 induction required NF-E2-related factor 2 function and phosphorylation of c-jun N-terminal kinase.We infer that AGO administration inhibits TNBS-induced colitis in mice through HO-1 induction in macrophages. Consequently, oral administration of AGOs might be an important therapeutic strategy for inflammatory bowel disease.