IDO: A Novel Endogenous Suppressor of Inflammation

描述（摘自申请人摘要）：风湿性关节炎（RA）是 其特征在于慢性进行性滑膜炎症和随后的 破坏关节结构。类风湿性滑膜炎的发病机制 涉及T淋巴细胞之间复杂的相互作用， 成纤维细胞样滑膜细胞（FLS）和炎性细胞因子网络。 基质金属蛋白酶（MMP）表达增加的FLS活化 和环氧合酶-2（考克斯-2）酶是血管翳形成的关键步骤， 组织侵入，并有助于催化初始和限速 必需氨基酸色氨酸（TRP）代谢的一步。IDO原因 耗尽可用的TRP，最终导致组织中的局部TRP饥饿，以及 降低血清中TRP浓度。IDO表达由干扰素-γ诱导 （IFN-γ）在多个细胞中，包括FLS。IDO活性在RA中升高， 其他慢性炎症状态，但这种酶的真正生理作用 仍然未知。我们实验室和其他机构的最新观察结果 研究人员指出，由IDO催化的TRP消耗产生了深刻的影响， 对免疫和炎症途径的影响。因此，我们现在建议， 作为一种新的内源性炎症抑制因子， 炎症性关节炎的病程。在这里，我们将研究IDO在以下方面的作用： 炎性关节炎三个相互关联的具体目标。具体目标1、 我们将确立IDO和TRP催化剂的根本重要性， IFN-γ抑制正常FLS中MMP和PGE产生，并确定 组成型IDO活化赋予转染细胞对以下的抗性： 体外炎症刺激。IDO介导的细胞机制 炎症反应的抑制将在具体目标2中研究。 在具体目标3中，我们将检查IDO功能在鼠体内的抑制是否 使用竞争性IDO抑制剂调节胶原诱导的关节炎， 实验性关节炎的过程IDO和TRP饥饿的潜力， 调节滑膜炎症反应的早期和晚期步骤， 一种基于TRP消耗的滑膜炎治疗方法， 很吸引人。

DESCRIPTION (Taken from the applicant's abstract): Rheumatoid arthritis (RA) is characterized by chronic progressive synovial inflammation and subsequent destruction of articular structures. The pathogenesis of rheumatoid synovitis involves complex interaction between T lymphocytes, autonomously activated fibroblast-like synovial cells (FLS) and networks of inflammatory cytokines. Activation of FLS with increased expression of matrix metalloproteinases (MMP) and cyclooxygenase-2 (Cox-2) enzymes are key steps in pannus formation and tissue invasion, and contribute to that catalyzes the initial and rate-limiting step in the metabolism of the essential amino acid tryptophan (TRP. IDO causes depletion of available TRP, culminating in local TRP starvation in tissue, and reduced TRP concentration in serum. IDO expression is induced by interferon-y (IFN-y) in multiple cells, including FLS. IDO activity is elevated in RA and other chronic inflammatory states, but the true physiologic role of this enzyme remains unknown. Recent observations from our laboratory and other investigators indicate that TRP depletion catalyzed by IDO exerts profound effects on immune and inflammatory pathways. We therefore now propose that IDO functions as a novel endogenous suppressor of inflammation, and modulates the course of inflammatory arthritis. Here we will examine the role of IDO in inflammatory arthritis in three interrelated Specific Aims. In Specific Aim 1, we will establish the fundamental importance of IDO and TRP catabolism in suppression of MMP and PGE production in normal FLS by IFN-y, and determine if constitutive IDO activation confers resistance of transfected cells to inflammatory stimuli in vitro. The cellular mechanisms underlying IDO-mediated suppression of inflammatory responses will be investigated in Specific Aim 2. In Specific Aim 3, we will examine if inhibition of IDO function in vivo murine collagen-induced arthritis using a competitive IDO inhibitor modulated the course of experimental arthritis. The potential of IDO and TRP starvation to modulate both early and late steps in the synovial inflammatory response makes an approach to synovitis treatment based on TRP depletion particularly appealing.