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¹ Department of Microbiology, ² Department of Pathology, ³ Department of Physiology, and ⁴ Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Korea
⁵ College of Animal Resource Sciences, Kangwon National University, Chunchon 200-701, Korea
⁶ Department of Oral Biochemistry, College of Dentistry, Chonnam National University, Gwangju 500-757, Korea
⁷ Glycomics Team, Division of Proteome Research, Korea Basic Science Institute, Daejeon 305-333, Korea
⁸ Institut National de la Santé et de la Recherche Médicale U773, Université Paris 7-Denis Diderot, Site Bichat, 75018 Paris, France
⁹ Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea

CORRESPONDENCE Eun-Kyeong Jo: hayoungj{at}cnu.ac.kr OR Dae-Yeul Yu: dyyu10{at}kribb.re.kr

Mammalian 2-Cys peroxiredoxin II (Prx II) is a cellular peroxidase that eliminates endogenous H₂O₂. 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 B 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 H₂O₂ 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.

Abbreviations used: Ab, antibody; Ad-CAT, adenoviral vectors that carry the catalase gene; Ad–Prx II, adenoviral vectors that carry the Prx II gene; ASK1, apoptosis signal–regulating kinase 1; BLP, bacterial lipoprotein; BMDM, bone marrow–derived macrophage; CL, chemiluminescence; DHE, dihydroethidium; DN, dominant negative; DPI, diphenylene iodonium; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal– regulated kinase; JNK, c-Jun N-terminal kinase; L-NAME, N-nitro-L-arginine methyl ester; L-NMMA, N^G-monomethyl-L-arginine; MAPK, mitogen-activated protein kinase; NAC, N-acetyl-L-cysteine; NADPH, nicotinamide adenine dinucleotide phosphate; PDGF, platelet-derived growth factor; PGN, peptidoglycan; Prx II, peroxiredoxin II; ROS, reactive oxygen species; SAPK, stress-activated protein kinase; TLR, Toll-like receptor; TRX, thioredoxin.

C.-S. Yang and D.-S. Lee contributed equally to this work.

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