Szántó Sándor, Koreny Tamás, Mikecz Katalin, Glant Tibor T, Szekanecz Zoltán, Varga John
Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Cohn Research Building, Room 708, 1735 W, Harrison, Chicago, IL 60612, USA.
Arthritis Res Ther. 2007;9(3):R50. doi: 10.1186/ar2205.
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-gamma 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.
吲哚胺2,3-双加氧酶（IDO）是参与必需氨基酸色氨酸分解代谢的初始限速酶之一。在培养细胞中，IDO的诱导会导致色氨酸耗竭和色氨酸饥饿。最近的研究表明，通过IDO调节色氨酸浓度在先天免疫反应中起基本作用。巨噬细胞和树突状细胞中γ干扰素诱导IDO会导致色氨酸耗竭，并抑制成纤维细胞、T细胞、B细胞和自然杀伤细胞的免疫介导激活。为了评估IDO在胶原诱导性关节炎（CIA）中的作用，CIA是一种以主要类似Th1的免疫反应为特征的类风湿性关节炎模型，在体内用1-甲基色氨酸（1-MT）抑制IDO的活性。结果显示，用1-MT处理的小鼠中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/色氨酸比值来确定的IDO活性在关节炎急性期增加，并且在未发生关节炎的胶原免疫小鼠中更高。与用赋形剂处理的关节炎小鼠相比，用1-MT处理导致关节炎小鼠的细胞免疫和体液免疫反应增强，并且向Th1的极化更占优势。结果表明，CIA的发展与小鼠IDO活性增加和色氨酸分解代谢增强有关。用1-MT阻断IDO会加重关节炎的严重程度并增强免疫反应。这些发现表明，IDO可能在CIA的负反馈中以及可能在类风湿性关节炎的发病机制中发挥重要的新作用。
