Criado Gabriel, Simelyte Egle, Inglis Julia J, Essex David, Williams Richard O
Kennedy Institute of Rheumatology, Imperial College London, London, UK.
Arthritis Rheum. 2009 May;60(5):1342-51. doi: 10.1002/art.24446.
Indoleamine 2,3 dioxygenase (IDO) is a catabolic enzyme that initiates the kynurenine pathway of tryptophan degradation and has immunomodulatory properties. The aim of this study was to investigate the regulation of collagen-induced arthritis by tryptophan catabolism mediated by IDO.
Arthritis was induced by immunization with type II collagen. After induction of arthritis, the expression of IDO was analyzed by quantitative reverse transcription-polymerase chain reaction. The effect of IDO deficiency on collagen-induced arthritis was assessed in vivo by administration of 1-methyltryptophan and clinical and histologic evaluation of IDO-deficient mice. The requirement for IDO activation was bypassed by administration of L-kynurenine.
IDO was induced in lymph node dendritic cells after collagen immunization. Systemic inhibition of tryptophan catabolism during active arthritis increased disease severity. Conversely, bypassing the requirement for tryptophan degradation by the administration of L-kynurenine resulted in amelioration of arthritis. Furthermore, IDO-deficient mice showed a higher incidence of arthritis and exacerbated disease severity compared with IDO-competent mice. Such increased disease activity in IDO-deficient mice correlated early with increased production of the proinflammatory cytokines interferon-gamma and interleukin-17 by lymph node T cells and later with increased infiltration of Th1 and Th17 cells in the inflamed joints.
Our data indicate that the induction of IDO controls the accumulation of Th1 and Th17 pathogenic T cells at the site of inflammation during collagen-induced arthritis. Therefore, manipulation of the kynurenine pathway of tryptophan degradation provides the potential for therapeutic intervention in rheumatoid arthritis.
吲哚胺2,3-双加氧酶（IDO）是一种分解代谢酶，可启动色氨酸降解的犬尿氨酸途径，并具有免疫调节特性。本研究旨在探讨由IDO介导的色氨酸分解代谢对胶原诱导性关节炎的调节作用。
用II型胶原免疫诱导关节炎。关节炎诱导后，通过定量逆转录-聚合酶链反应分析IDO的表达。通过给予1-甲基色氨酸以及对IDO缺陷小鼠进行临床和组织学评估，在体内评估IDO缺陷对胶原诱导性关节炎的影响。通过给予L-犬尿氨酸绕过IDO激活的需求。
胶原免疫后，淋巴结树突状细胞中诱导了IDO。在活动性关节炎期间对色氨酸分解代谢进行全身抑制会增加疾病严重程度。相反，通过给予L-犬尿氨酸绕过色氨酸降解的需求可改善关节炎。此外，与具有IDO功能的小鼠相比，IDO缺陷小鼠的关节炎发病率更高，疾病严重程度加剧。IDO缺陷小鼠中这种增加的疾病活动早期与淋巴结T细胞产生促炎细胞因子干扰素-γ和白细胞介素-17增加有关，后期与炎症关节中Th1和Th17细胞浸润增加有关。
我们的数据表明，IDO的诱导在胶原诱导性关节炎期间控制了炎症部位Th1和Th17致病性T细胞的积累。因此，操纵色氨酸降解的犬尿氨酸途径为类风湿性关节炎的治疗干预提供了潜力。
