Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice
Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice
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DOI：
10.1053/j.gastro.2003.08.031
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发表时间：
2003-12-01
期刊：
影响因子：
29.4
通讯作者：
Stenson, WF
中科院分区：
文献类型：
--
作者：
Gurtner, GJ;Newberry, RD;Stenson, WF
背景和目标：吲哚胺2，3-双加氧酶（IDO）是干扰素γ诱导的细胞内酶，通过色氨酸降解抑制淋巴细胞增殖。IDO在哺乳动物肠中高度表达。我们试图确定IDO是否在辅助T细胞1（Th 1）介导的三硝基苯磺酸（TNBS）结肠炎模型中发挥调节作用。方法：将TNBS与安慰剂或特异性IDO抑制剂一起直肠内给予SJL/J小鼠沿着。通过Western印迹和实时定量PCR评估IDO蛋白和mRNA表达。在存在和不存在IFN-γ的情况下，分离、分级和培养结肠固有层单核细胞（LPMNC），以确定表达IDO的细胞类型。结果：IDO由固有层专职抗原提呈细胞表达。TNBS结肠炎的诱导导致IDO mRNA（P = 0.005）和蛋白质表达的显著增加。TNBS结肠炎期间的IDO抑制导致80%的死亡率，而安慰剂治疗的动物为10%（P = 0.0089）。与安慰剂治疗的动物相比，IDO抑制导致组织学和形态学上更严重的结肠炎（P < 0.05），并显著增加结肠促炎细胞因子表达。结论：IDO在正常结肠中表达，并且在TNBS结肠炎的情况下上调。TNBS结肠炎期间IDO的抑制导致死亡率增加和正常炎症反应的增强。这些发现表明IDO在胃肠道内Th 1应答的下调中起重要作用。
Background & Aims: Indoleamine 2,3-dioxygenase (IDO), an interferon gamma-induced intracellular enzyme, inhibits lymphocyte proliferation through tryptophan degradation. IDO is highly expressed in the mammalian intestine. We sought to determine whether IDO played a regulatory role in the T-cell helper 1 (Th1)-mediated trinitrobenzene sulfonic acid (TNBS) model of colitis. Methods: Intrarectal TNBS was given to SJL/J mice along with either placebo or a specific IDO inhibitor. IDO protein and mRNA expression were assessed by Western blotting and real-time PCR. Colonic lamina propria mononuclear cells (LPMNCs) were isolated, fractionated, and cultured, in the presence and absence of IFN-gamma, to determine the cell type(s) expressing IDO. Results: IDO is expressed by professional antigen-presenting cells in the lamina propria. Induction of TNBS colitis resulted in a significant increase in IDO mRNA (P = 0.005) and protein expression. IDO inhibition during TNBS colitis resulted in an 80% mortality compared with 10% for placebo-treated animals (P = 0.0089). IDO inhibition resulted in a more severe colitis both histologically and morphologically (P < 0.05) and significantly increased colonic proinflammatory cytokine expression compared with placebo-treated animals. Conclusions: IDO is expressed in the normal colon and is up-regulated in the setting of TNBS colitis. Inhibition of IDO during TNBS colitis resulted in increased mortality and an augmentation of the normal inflammatory response. These findings suggest that IDO plays an important role in the down-regulation of Th1 responses within the gastrointestinal tract.