Division of Gastroenterology, Washington University, St Louis, MO 63110, USA.
J Immunol. 2010 Apr 1;184(7):3907-16. doi: 10.4049/jimmunol.0900291. Epub 2010 Feb 24.
The chronic inflammatory bowel diseases are characterized by aberrant innate and adaptive immune responses to commensal luminal bacteria. In both human inflammatory bowel disease and in experimental models of colitis, there is an increased expression of the enzyme IDO. IDO expression has the capacity to exert antimicrobial effects and dampen adaptive immune responses. In the murine trinitrobenzene sulfonic acid 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 (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-oligodeoxynucleotide. Signaling required for intestinal IDO-1 induction involves IFN-dependent pathways, as IDO-1 was not induced in STAT-1 knockout mice. Using both the trinitrobenzene sulfonic acid and dextran sodium sulfate models of colitis, we show the importance of IDO-1s induction in limiting colitis severity. The clinical parameters and histological 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-oligodeoxynucleotide 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.
慢性炎症性肠病的特征是对共生腔内细菌的先天和适应性免疫反应异常。在人类炎症性肠病和结肠炎的实验模型中，IDO 酶的表达增加。IDO 的表达具有发挥抗菌作用和抑制适应性免疫反应的能力。在三硝基苯磺酸诱导的结肠炎小鼠模型中，抑制这种酶会导致疾病严重程度恶化，这表明 IDO 作为一种自然的限制结肠炎的机制发挥作用。在这项研究中，我们表明 TLR-9 激动剂、免疫刺激（ISS）DNA 诱导 IDO-1 的表达，这对其限制结肠炎的能力至关重要。ISS DNA 诱导肠道 IDO-1 的表达，但不诱导最近描述的同工酶 IDO-2。这种诱导发生在肠上皮细胞和固有层中 CD11c(+)和 CD11b(+)细胞的亚群中，在 ISS-寡脱氧核苷酸后也会增加。肠 IDO-1 诱导所需的信号涉及 IFN 依赖性途径，因为 STAT-1 敲除小鼠中不诱导 IDO-1。我们使用三硝基苯磺酸和葡聚糖硫酸钠诱导的结肠炎模型，表明 IDO-1 的诱导在限制结肠炎严重程度方面的重要性。这些模型中的临床参数和组织学相关性通过 TLR-9 激动剂的给药得到改善；然而，当抑制 IDO 的功能时，ISS-寡脱氧核苷酸的结肠炎限制作用被消除。这些发现支持了靶向诱导 IDO-1 作为一种治疗策略的可能性，值得进一步研究用于治疗肠道炎症性疾病。
