Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis.
Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis.
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DOI：
10.4049/jimmunol.0900291
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发表时间：
2010-04-01
期刊：
影响因子：
--
通讯作者：
Stenson WF
中科院分区：
文献类型：
--
作者：
Ciorba MA;Bettonville EE;McDonald KG;Metz R;Prendergast GC;Newberry RD;Stenson WF
慢性炎症性肠病的特点是对共生细菌产生异常的先天和获得性免疫反应。在人类IBD和实验性结肠炎模型中，吲哚胺2，3双加氧酶(IDO)的表达都增加。IDO的表达具有抗菌和抑制获得性免疫反应的能力。在结肠炎的小鼠TNBS模型中，抑制这种酶会导致疾病严重程度的恶化，这表明IDO在限制结肠炎方面起到了自然的突破作用。在这项研究中，我们表明，TLR-9激动剂免疫刺激DNA(ISS-DNA)对IDO-1的诱导对其结肠炎限制能力具有关键作用。ISS-DNA诱导肠道表达IDO-1，但不能诱导最近描述的辅酶IDO-2。这种诱导发生在固有层的上皮细胞和CD11c+和CD11b+细胞亚群中，ISS-ODN后这些细胞的数量也增加了。肠道IDO-1诱导所需的信号涉及干扰素依赖的通路，因为在STAT-1基因敲除小鼠中没有诱导IDO-1。使用结肠炎的TNBS和DSS模型，我们证明了IDO-1S诱导在限制结肠炎严重程度中的重要性。给予TLR-9激动剂可以改善结肠炎的临床参数和组织学相关性，但当IDO的功能被抑制时，ISS-ODN的结肠炎抑制作用被取消。这些发现支持靶向诱导IDO-1是一种值得进一步研究的方法，作为肠道炎症疾病的治疗策略。
The chronic inflammatory bowel diseases are characterized by aberrant innate and adaptive immune responses to commensal luminal bacteria. In both human IBD and in experimental models of colitis there is an increased expression of the enzyme indoleamine 2,3 dioxygenase (IDO). IDO expression has the capacity to exert antimicrobial effects and dampen adaptive immune responses. In the murine TNBS model of colitis, inhibition of this enzyme leads to worsened disease severity suggesting that IDO acts as a natural break in limiting colitis. In this investigation we show that induction of IDO-1 by a TLR-9 agonist, immunostimulatory-DNA (ISS-DNA), critically contributes to its colitis limiting capacities. ISS-DNA induces intestinal expression of IDO-1, but not the recently described paralog enzyme IDO-2. This induction occurred in both epithelial cells and in subsets of CD11c+ and CD11b+ cells of the lamina propria which also increase after ISS-ODN. Signaling required for intestinal IDO-1 induction involves interferon dependent pathways, as IDO-1 was not induced in STAT-1 knockout mice. Using both the TNBS and DSS models of colitis we show the importance of IDO-1s induction in limiting colitis severity. The clinical parameters and histologic correlates of colitis in these models were improved by administration of the TLR-9 agonist; however, when the function of IDO is inhibited, the colitis limiting effects of ISS-ODN were abrogated. These findings support the possibility that targeted induction of IDO-1 is an approach deserving further investigation as a therapeutic strategy for diseases of intestinal inflammation.
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影响因子：
15.9
作者：
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29.4
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DOI：
10.1016/j.biocel.2008.01.005
发表时间：
2009-03-01
影响因子：
4
作者：
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通讯作者：
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