Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock.
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.
Yang
Chul-Su
CS
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea.
Lee
Dong-Seok
DS
Song
Chang-Hwa
CH
An
Se-Jin
SJ
Li
Shengjin
S
Kim
Jin-Man
JM
Kim
Cuk Seong
CS
Yoo
Dae Goon
DG
Jeon
Byeong Hwa
BH
Yang
Hee-Young
HY
Lee
Tae-Hoon
TH
Lee
Zee-Won
ZW
El-Benna
Jamel
J
Yu
Dae-Yeul
DY
Jo
Eun-Kyeong
EK
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004731:Endotoxins / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010544:Peroxidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054464:Peroxiredoxins; D012769:Shock / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D004731:Endotoxins; D008070:Lipopolysaccharides; D010544:Peroxidases; D054464:Peroxiredoxins