Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-κB
Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-κB
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DOI：
10.1002/eji.200636651
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发表时间：
2007-04-01
影响因子：
5.4
通讯作者：
Speert, David P.
中科院分区：
文献类型：
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作者：
Bylund, Johan;MacDonald, Kelly L.;Speert, David P.
细胞内NADPH-氧化酶产生的活性氧种(ROS)是吞噬杀灭吞噬微生物的关键物质，并被认为是多种过程中的信号分子。例如，ROS被认为参与了转录因子NF-kappa B的激活，该转录因子在炎症刺激下调节促炎细胞因子的产生。一些研究表明，NADPH-氧化酶的抑制剂干扰了核因子-kappaB的激活和促炎细胞因子的产生。奇怪的是，慢性肉芽肿病(CGD)是一种免疫缺陷，其特征是无法产生ROS，不仅容易发生严重感染，而且经常发生各种炎症并发症，表明炎症反应过度。在这里，我们显示了人类CGD白细胞表现出高度炎症表型，在Toll样受体激动剂的刺激下，促炎症细胞因子的产生增加。在CGD小鼠的单个核细胞(gp91(Phox-/-))中也有明显的炎症表型，但在NADPH-氧化酶抑制剂二苯乙二胺存在的对照细胞中则不明显，这可能反映了该抑制剂的NADPH-氧化酶非依赖性作用。此外，我们发现参与核因子-kappaB激活的主要步骤在人CGD细胞中是完整的。这些数据表明，ROS对核因子-kappaB的激活不是必需的，它们的产生甚至可能减轻炎症。
Reactive oxygen species (ROS) generated by the cellular NADPH-oxidase are crucial for phagocytic killing of ingested microbes and have been implicated as signaling molecules in various processes. For example, ROS are thought to be involved in activation of the transcription factor NF-kappa B, central for mediating production of proinflammatory cytokines in response to inflammatory stimuli. Several studies have demonstrated that inhibitors of the NADPH-oxidase interfere with NF-kappa B activation and production of proinflammatory cytokines. Curiously, patients with chronic granulomatous disease (CGD), an immunodeficiency characterized by an inability to produce ROS, are not only predisposed to severe infections, but also frequently develop various inflammatory complications indicative of exaggerated inflammatory responses. Here, we show that human CGD leukocytes display a hyperinflammatory phenotype with increased production of proinflammatory cytokines in response to stimulation with Toll-like receptor agonists. The hyperinflammatory phenotype was also evident in mononuclear cells from CGD mice (gp91(phox-/-)), but not in control cells in the presence of NADPH-oxidase inhibitor diphenyleneiodonium, probably reflecting NADPH-oxidase-independent effects of the inhibitor. Furthermore, we show that the major steps involved in NF-kappa B activation were intact in human CGD cells. These data indicate that ROS were nonessential for activation of NF-kappa B and their production may even attenuate inflammation.