IDO: A Novel Endogenous Suppressor of Inflammation

描述(摘自申请人的摘要)：类风湿性关节炎(RA) 以慢性进行性滑膜炎症和随后的 关节结构的破坏。类风湿滑膜炎的发病机制 涉及T淋巴细胞之间的复杂相互作用，自主激活 成纤维细胞样滑膜细胞(FLS)和炎性细胞因子网络。 FLS激活与基质金属蛋白酶(MMPs)表达增加 环氧合酶-2(COX-2)酶是血管疙瘩形成和发展的关键步骤。 组织入侵，并在其中催化了初始和限速 参与必需氨基酸色氨酸(Trp)的代谢。IDO原因 可用色氨酸的消耗，最终导致组织中的局部色氨酸饥饿，以及 降低血清色氨酸浓度。干扰素-γ诱导IDO的表达 (干扰素-γ)在多个细胞中，包括FLS。类风湿性关节炎患者IDO活性升高 其他慢性炎症状态，但这种酶的真正生理作用 仍然不为人知。我们实验室和其他机构最近的观察结果 研究人员指出，IDO催化的色氨酸耗竭作用深远 对免疫和炎症途径的影响。因此，我们现在建议IDO 作为一种新的内源性炎症抑制因子，并调节 炎性关节炎的病程。在这里，我们将研究IDO在 炎症性关节炎有三个相互关联的具体目标。在具体目标1中， 我们将确立IDO和Trp分解代谢的根本重要性 干扰素-γ抑制正常FLS中基质金属蛋白酶和前列腺素E的产生 结构性IDO激活使转基因细胞对 体外炎性刺激。IDO介导的细胞机制 抑制炎症反应将在特定目标2中进行研究。 在特定的目标3中，我们将检查体内抑制IDO功能的小鼠 使用竞争性IDO抑制剂的胶原蛋白诱导的关节炎调节 实验性关节炎的病程。IDO和Trp饥饿对 调节滑膜炎症反应的早期和晚期步骤 一种基于Trp耗竭的滑膜炎治疗方法 很有吸引力。

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.