Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice.
Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice.
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DOI：
10.1186/ar2205
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发表时间：
2007
影响因子：
4.9
通讯作者：
Varga J
中科院分区：
文献类型：
--
作者：
Szántó S;Koreny T;Mikecz K;Glant TT;Szekanecz Z;Varga J
吲哚胺2，3-双加氧酶（IDO）是参与色氨酸催化的起始酶和限速酶之一。在培养的细胞中，IDO的诱导导致色氨酸耗尽和色氨酸饥饿。最近的研究表明，通过IDO调节色氨酸浓度在先天免疫应答中起着重要作用。巨噬细胞和树突细胞中干扰素-γ诱导IDO导致色氨酸耗竭并抑制成纤维细胞和T、B和自然杀伤细胞的免疫介导的活化。为了评估IDO在胶原诱导的关节炎（CIA）中的作用，胶原诱导的关节炎（CIA）是一种以主要Th 1样免疫应答为特征的类风湿性关节炎模型，IDO的活性在体内被1-甲基-色氨酸（1-MT）抑制。结果显示，1-MT治疗的小鼠CIA的发病率和严重程度显著增加。通过测量血清中犬尿氨酸/色氨酸比率的水平确定的IDO活性在关节炎的急性期增加，并且在未发展关节炎的胶原免疫小鼠中更高。与溶剂治疗的关节炎小鼠相比，1-MT治疗导致关节炎小鼠的细胞和体液免疫应答增强，并且向Th 1的极化更占主导地位。结果表明，CIA的发展与IDO活性增加和色氨酸催化活性增强有关。用1-MT阻断IDO可加重关节炎的严重程度并增强免疫反应。这些结果提示IDO可能在CIA的负反馈中发挥重要而新颖的作用，并可能在类风湿关节炎的发病机制中发挥作用。
Indoleamine 2,3-dioxygenase (IDO) is one of the initial and rate-limiting enzymes involved in the catabolism of the essential amino acid tryptophan. In cultured cells, the induction of IDO leads to depletion of tryptophan and tryptophan starvation. Recent studies suggest that modulation of tryptophan concentration via IDO plays a fundamental role in innate immune responses. Induction of IDO by interferon-γ in macrophages and dendritic cells results in tryptophan depletion and suppresses the immune-mediated activation of fibroblasts and T, B, and natural killer cells. To assess the role of IDO in collagen-induced arthritis (CIA), a model of rheumatoid arthritis characterized by a primarily Th1-like immune response, activity of IDO was inhibited by 1-methyl-tryptophan (1-MT) in vivo. The results showed significantly increased incidence and severity of CIA in mice treated with 1-MT. Activity of IDO, as determined by measuring the levels of kynurenine/tryptophan ratio in the sera, was increased in the acute phase of arthritis and was higher in collagen-immunized mice that did not develop arthritis. Treatment with 1-MT resulted in an enhanced cellular and humoral immune response and a more dominant polarization to Th1 in mice with arthritis compared with vehicle-treated arthritic mice. The results demonstrated that development of CIA was associated with increased IDO activity and enhanced tryptophan catabolism in mice. Blocking IDO with 1-MT aggravated the severity of arthritis and enhanced the immune responses. These findings suggest that IDO may play an important and novel role in the negative feedback of CIA and possibly in the pathogenesis of rheumatoid arthritis.
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影响因子：
20.3
作者：
Boasso, A;Herbeuval, JP;Shearer, GM
通讯作者：
Shearer, GM
影响因子：
15.9
作者：
VARGA, J;YUFIT, T;BROWN, RR
通讯作者：
BROWN, RR
影响因子：
4.4
作者：
Zhu, Lingqiao;Ji, Fang;Zhang, Yanyun
通讯作者：
Zhang, Yanyun
影响因子：
4.6
作者：
Harris, HE;Liljestrom, M;Klareskog, L
通讯作者：
Klareskog, L
影响因子：
4.6
作者：
MarinovaMutafchieva, L;Williams, RO;Maini, RN
通讯作者：
Maini, RN