Blockade of Indoleamine 2,3-Dioxygenase Protects Mice against Lipopolysaccharide-Induced Endotoxin Shock
Blockade of Indoleamine 2,3-Dioxygenase Protects Mice against Lipopolysaccharide-Induced Endotoxin Shock
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DOI：
10.4049/jimmunol.0803104
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发表时间：
2009-03-01
影响因子：
4.4
通讯作者：
Park, Yeong-Min
中科院分区：
文献类型：
--
作者：
Jung, In Duk;Lee, Min-Goo;Park, Yeong-Min
抑制过度的全身炎症反应是治疗内毒素败血症的一种有前途且有效的策略。吲哚胺 2,3-双加氧酶 (IDO) 是色氨酸分解代谢的限速酶，可能在各种炎症性疾病中发挥关键作用。在这项研究中，我们报告了 IDO 在与内毒素休克相关的免疫反应失调中发挥的关键作用。我们发现 IDO 敲除 (IDO-/-) 小鼠和经 1-甲基-D-色氨酸处理的内毒素休克小鼠的细胞因子、TNF-α、IL-6 和 IL-12 水平降低，而 IL-10 水平升高。 IDO 的阻断被认为可以促进 LPS 诱导的内毒素休克中宿主的生存，但人们对内毒素休克期间调节 IDO 表达的分子机制知之甚少。在体外和体内，树突状细胞和脾树突状细胞中IDO表达被外源IL-12增加，但被外源IL-10减少。有趣的是，虽然 LPS 诱导的血清中 IL-12 水平高于 IL-10，但攻击后血清 IL-12 和 IL-10 之间的平衡在 IDO-/- 中发生逆转。或1-甲基-D-色氨酸处理的小鼠。我们的研究结果表明，对内毒素休克的有害免疫反应可能通过 IDO 调节发生。通过阻断 IDO 恢复 IL-12 和 IL-10 平衡是脓毒症治疗的潜在策略。免疫学杂志，2009，182：3146-3154。
Suppression of an excessive systemic inflammatory response is a promising and potent strategy for treating endotoxic sepsis. Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. In this study, we report a critical role for IDO in the dysregulated immune response associated with endotoxin shock. We found that IDO knockout (IDO-/-) mice and 1-methyl-D-tryptophan-treated, endotoxin-shocked mice had decreased levels of the cytokines, TNF-alpha, IL-6, and IL-12, and enhanced levels of IL-10. Blockade of IDO is thought to promote host survival in LPS-induced endotoxin shock, yet little is known about the molecular mechanisms that regulate IDO expression during endotoxin shock. In vitro and in vivo, IDO expression was increased by exogenous IL-12, but decreased by exogenous IL-10 in dendritic cells and splenic dendritic cells. Interestingly, whereas LPS-induced IL-12 levels in serum were higher than those of IL-10, the balance between serum IL-12 and IL-10 following challenge became reversed in IDO-/-. or 1-methyl-D-tryptophan-treated mice. Our findings demonstrate that the detrimental immune response to endotoxin shock may occur via IDO modulation. Restoring the IL-12 and IL-10 balance by blocking IDO represents a potential strategy for sepsis treatment. The Journal of Immunology, 2009, 182: 3146-3154.