Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock

Mammalian 2-Cys peroxiredoxin type II (Prx II) is a cellular peroxidase that eliminates endogenous hydrogen peroxide (H2O2). The involvement of Prx II in the regulation of lipopolysaccharide (LPS) signaling is poorly understood. In this report, we show that LPS induces significantly enhanced inflammatory events, which include the signaling molecules NF-κB and mitogen-activated protein-kinase (MAPK), in Prx II-deficient macrophages. This effect of LPS was mediated by the robust upregulation of the reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and the phosphorylation of p47Phox. 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. 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.