NITRIC-OXIDE - CYTOKINE-REGULATION OF NITRIC-OXIDE IN HOST-RESISTANCE TO INTRACELLULAR PATHOGENS
NITRIC-OXIDE - CYTOKINE-REGULATION OF NITRIC-OXIDE IN HOST-RESISTANCE TO INTRACELLULAR PATHOGENS
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DOI：
10.1016/0165-2478(94)00158-8
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发表时间：
1994-12-01
影响因子：
4.4
通讯作者：
NACY, CA
中科院分区：
文献类型：
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作者：
GREEN, SJ;SCHELLER, LF;NACY, CA
为了了解不同组织中的一氧化氮 (NO) 合成是如何在这些组织内的细胞对抗细胞内病原体时受到控制的，我们检查了三种截然不同的实验小鼠模型，这些模型旨在研究寄生虫与宿主的相互作用：巨噬细胞杀死大型利什曼原虫；牛杆菌 (BCG) 对兔热病（Francisella tularensis）的非特异性保护；以及针对伯氏疟原虫肝性疟疾的特异性疫苗诱导保护。每个模型寄生虫和宿主系统都提供了有关 NO 在感染过程中的来源和作用以及诱导或抑制其产生的因素的信息。巨噬细胞针对 L. Major 的抗菌活性的体外测定确定了参与调节 NO 介导的细胞内原生动物杀伤的细胞因子。 L. Major 在受感染的巨噬细胞中诱导产生两种竞争性细胞因子：（I）寄生虫激活肿瘤坏死因子（TNF）基因，并且干扰素-γ（IFN-γ）的存在增强了 TNF 蛋白的产生。然后 TNF 作为自分泌信号来放大 IFN-γ 诱导的 NO 产生； (2) 寄生虫上调转化生长因子-β (TGF-β) 的产生，从而阻止 IFN-γ 诱导的 NO 产生。寄生虫诱导的 TNF（寄生虫破坏）还是 TGF-β（寄生虫存活）占主导地位，取决于感染时 IFN-γ 的存在和数量。牛分枝杆菌 (BCG) 证明了体内 NO 产生与宿主对感染的抵抗力之间的关系。这些研究证实，IFN-γ和TNF都是诱导NO介导的体内非特异性宿主防御所必需的。在这些研究中，推测 NO 的来源是活化的巨噬细胞，然而，感染寄生虫的其他细胞也可以被刺激产生 NO。在研究受辐射子孢子诱导的对疟疾的获得性免疫力时，我们发现疟疾特异性CD8+T细胞提供的IFN-γ刺激子孢子感染的肝细胞产生NO，从而破坏受感染的肝细胞或这些细胞内的伯氏疟原虫。
To discover how nitric oxide (NO) synthesis is controlled in different tissues as cells within these tissues combat intracellular pathogens, we examined three distinctively different experimental murine models designed for studying parasite-host interactions: macrophage killing of Leishmania major; nonspecific protection against tularemia (Francisella tularensis) by My cobacterium bovis (BCG); and specific vaccine-induced protection against hepatic malaria with Plasmodium berghei. Each model parasite and host system provides information on the source and role of NO during infection and the factors that induce or inhibit its production. The in vitro assay for macrophage antimicrobial activity against L. major identified cytokines involved in regulating NO-mediated killing of this intracellular protozoan. L. major induced the production of two competing cytokines in infected macrophages: (I) the parasite activated the gene for tumor necrosis factor (TNF), and production of TNF protein was enhanced by the presence of interferon-gamma (IFN-gamma). TNF then acted as a autocrine signal to amplify IFN-gamma-induced production of NO; and (2) the parasite upregulated production of transforming growth factor-beta (TGF-beta), which blocked IFN-gamma-induced production of NO. Whether parasite-induced TNF (parasite destruction) or TGF-beta (parasite survival) prevailed depended upon the presence and quantity of IFN-gamma at the time of infection. The relationship between NO production in vivo and host resistance to infection was demonstrated with M bovis (BCG). These studies confirmed that both IFN-gamma and TNF are required for induction of NO-mediated nonspecific host defense in vivo. The presumed source of NO in these studies was the activated macrophage, however, other cells infected with parasites can also be stimulated to produce NO. In studying acquired immunity to malaria induced by irradiated sporozoites, we found that IFN-gamma provided by malaria-specific CD8(+) T cells stimulated sporozoite-infected hepatocytes to produce NO for destruction of either infected hepatocytes or the parasite, P. berghei, within these cells.