POLIOVIRUS INDUCES INDOLEAMINE-2,3-DIOXYGENASE AND QUINOLINIC ACID SYNTHESIS IN MACAQUE BRAIN
POLIOVIRUS INDUCES INDOLEAMINE-2,3-DIOXYGENASE AND QUINOLINIC ACID SYNTHESIS IN MACAQUE BRAIN
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DOI：
10.1096/fasebj.6.11.1322853
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发表时间：
1992-08-01
期刊：
影响因子：
4.8
通讯作者：
VICKERS, JH
中科院分区：
文献类型：
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作者：
HEYES, MP;SAITO, K;VICKERS, JH
神经毒素喹啉酸在脑内的积累发生在许多患有炎症性神经系统疾病的患者中，并且可能具有神经病理学意义。喹啉酸的产生被认为反映了中枢神经系统内反应细胞和炎症细胞浸润中细胞因子对吲哚胺 2,3-双加氧酶的局部诱导。为了检验这一假设，猕猴接受了脊髓灰质炎病毒的椎管内注射，作为局部炎症性神经疾病的模型。 17天后，脊髓和脑脊液中的脊髓吲哚胺2,3-双加氧酶活性和喹啉酸浓度均随着脊髓炎症反应和神经损伤的程度以及运动麻痹的严重程度成比例地增加。脊髓和脑脊液中喹啉酸的绝对浓度超过了体外报告的杀死脊髓神经元的水平。脊髓灰质炎病毒目标区域顶叶皮层的吲哚胺 2,3-双加氧酶活性和喹啉酸浓度也出现较小程度的增加。额叶皮层不是脊髓灰质炎病毒的目标，在额叶皮层中，吲哚胺 2,3-双加氧酶没有受到影响。使用针对人吲哚胺 2,3-双加氧酶的单克隆抗体来观察主要存在于脊髓灰质炎病毒感染的脊髓灰质中的吲哚胺 2,3-双加氧酶以及局部炎症病变。巨噬细胞/单核细胞在体外从[C-13(6)]L-色氨酸合成[C-13(6)]喹啉酸，特别是在受到干扰素-γ刺激时。体外接种脊髓灰质炎病毒的猕猴的脊髓切片也将 [C-13(6)]L-色氨酸转化为 [C-13(6)]喹啉酸。我们得出的结论是，中枢神经系统内 L-色氨酸局部合成喹啉酸是在吲哚胺-2,3-双加氧酶的诱导后进行的，特别是在巨噬细胞/小胶质细胞内。鉴于免疫刺激与神经毒性量的喹啉酸合成之间的联系，我们建议减轻局部炎症、减少神经活性犬尿氨酸途径代谢物合成的策略或干扰喹啉酸神经毒性的药物为炎症性神经系统疾病的治疗提供新方法。
Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of patients with inflammatory neurologic disease and may be of neuropathologic significance. The production of quinolinic acid was postulated to reflect local induction of indoleamine 2,3-dioxygenase by cytokines in reactive cells and inflammatory cell infiltrates within the central nervous system. To test this hypothesis, macaques received an intraspinal injection of poliovirus as a model of localized inflammatory neurologic disease. Seventeen days later, spinal cord indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations in spinal cord and cerebrospinal fluid were both increased in proportion to the degree of inflammatory responses and neurologic damage in the spinal cord, as well as the severity of motor paralysis. The absolute concentrations of quinolinic acid achieved in spinal cord and cerebrospinal fluid exceeded levels reported to kill spinal cord neurons in vitro. Smaller increases in indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations also occurred in parietal cortex, a poliovirus target area. In frontal cortex, which is not a target for poliovirus, indoleamine 2,3-dioxygenase was not affected. A monoclonal antibody to human indoleamine 2,3-dioxygenase was, used to visualize indoleamine 2,3-dioxygenase predominantly in grey matter of poliovirus-infected spinal cord, in conjunction with local inflammatory lesions. Macrophage/monocytes in vitro synthesized [C-13(6)]quinolinic acid from [C-13(6)]L-tryptophan, particularly when stimulated by interferon-gamma. Spinal cord slices from poliovirus-inoculated macaques in vitro also converted [C-13(6)]L-tryptophan to [C-13(6)]quinolinic acid. We conclude that local synthesis of quinolinic acid from L-tryptophan within the central nervous system follows the induction of indoleamine-2,3-dioxygenase, particularly within macrophage/microglia. In view of this link between immune stimulation and the synthesis of neurotoxic amounts of quinolinic acid, we propose that attenuation of local inflammation, strategies to reduce the synthesis of neuroactive kynurenine pathway metabolites, or drugs that interfere with the neurotoxicity of quinolinic acid offer new approaches to therapy in inflammatory neurologic disease.