Yang Chul-Su, Lee Dong-Seok, Song Chang-Hwa, An Se-Jin, Li Shengjin, Kim Jin-Man, Kim Cuk Seong, Yoo Dae Goon, Jeon Byeong Hwa, Yang Hee-Young, Lee Tae-Hoon, Lee Zee-Won, El-Benna Jamel, Yu Dae-Yeul, Jo Eun-Kyeong
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea.
J Exp Med. 2007 Mar 19;204(3):583-94. doi: 10.1084/jem.20061849. Epub 2007 Feb 26.
Mammalian 2-Cys peroxiredoxin II (Prx II) is a cellular peroxidase that eliminates endogenous H(2)O(2). The involvement of Prx II in the regulation of lipopolysaccharide (LPS) signaling is poorly understood. In this report, we show that LPS induces substantially enhanced inflammatory events, which include the signaling molecules nuclear factor kappaB and mitogen-activated protein kinase (MAPK), in Prx II-deficient macrophages. This effect of LPS was mediated by the robust up-regulation of the reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and the phosphorylation of p47(phox). Furthermore, challenge with LPS induced greater sensitivity to LPS-induced lethal shock in Prx II-deficient mice than in wild-type mice. Intravenous injection of Prx II-deficient mice with the adenovirus-encoding Prx II gene significantly rescued mice from LPS-induced lethal shock as compared with the injection of a control virus. The administration of catalase mimicked the reversal effects of Prx II on LPS-induced inflammatory responses in Prx II-deficient cells, which suggests that intracellular H(2)O(2) is attributable, at least in part, to the enhanced sensitivity to LPS. These results indicate that Prx II is an essential negative regulator of LPS-induced inflammatory signaling through modulation of ROS synthesis via NADPH oxidase activities and, therefore, is crucial for the prevention of excessive host responses to microbial products.
哺乳动物双半胱氨酸过氧化物酶II（Prx II）是一种可清除内源性过氧化氢（H₂O₂）的细胞过氧化物酶。目前对Prx II在脂多糖（LPS）信号调节中的作用了解甚少。在本报告中，我们发现LPS在Prx II缺陷型巨噬细胞中可显著增强炎症反应事件，其中包括信号分子核因子κB和丝裂原活化蛋白激酶（MAPK）。LPS的这种作用是由产生活性氧（ROS）的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的强烈上调以及p47（phox）磷酸化介导的。此外，与野生型小鼠相比，LPS刺激使Prx II缺陷型小鼠对LPS诱导的致死性休克更敏感。与注射对照病毒相比，给Prx II缺陷型小鼠静脉注射编码Prx II基因的腺病毒可显著使小鼠免于LPS诱导的致死性休克。给予过氧化氢酶可模拟Prx II对Prx II缺陷型细胞中LPS诱导的炎症反应的逆转作用，这表明细胞内H₂O₂至少部分归因于对LPS敏感性的增强。这些结果表明，Prx II是LPS诱导炎症信号的重要负调节因子，通过调节NADPH氧化酶活性来调控ROS合成，因此对于预防宿主对微生物产物的过度反应至关重要。
