Redox regulation of lipopolysaccharide-mediated sulfiredoxin induction, which depends on both AP-1 and Nrf2.
Sulfiredoxin (Srx) is an enzyme that catalyzes the reduction of cysteine sulfinic acid of hyperoxidized peroxiredoxins and exerts a protective antioxidant role. Here we investigated the regulatory mechanism of Srx induction by lipopolysaccharide (LPS) in mouse macrophages. LPS up-regulated Srx expression on the transcriptional level. The promoter region of the Srx gene contained putative NF-κB and AP-1 (activator protein-1) sites, and the proximal site of three AP-1 sites was embedded within the antioxidant response element (ARE), a cis-acting element for Nrf2 (nuclear factor erythroid 2-related factor). Mutational analysis of the Srx promoter revealed that Srx induction is dependent on AP-1 sites and ARE but not on NF-κB sites. Consistently, both transcription factors, AP-1 and Nrf2, were required for LPS-mediated Srx induction, as revealed by chromatin immunoprecipitation using antibodies specific for c-Jun and c-Fos and little Srx induction in Nrf2-null bone marrow-derived macrophages. Among mitogen-activated protein kinases that mediate the signal transduction by LPS, JNK played a major role in Srx induction. Moreover, chemical antioxidants, such as N-acetylcysteine and butylated hydroxyanisole, and the NADPH oxidase inhibitor diphenyleneiodonium inhibited Srx induction as well as generation of reactive oxygen species, both of which were also suppressed in Nox2 (NADPH oxidase 2)-deficient bone marrow-derived macrophages. These results suggest that LPS-mediated Srx induction is dependent on both AP-1 and Nrf2, which is regulated by Nox2-derived reactive oxygen species.
Kim
Hojin
H
Department of Life Science, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 120-750, Korea.
Jung
Yuyeon
Y
Shin
Bong Soo
BS
Kim
Hyeryeon
H
Song
Hyunsook
H
Bae
Soo Han
SH
Rhee
Sue Goo
SG
Jeong
Woojin
W
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002384:Catalysis; D002460:Cell Line; D003545:Cysteine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000096:biosynthesis* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D002083:Butylated Hydroxyanisole; C007517:diphenyleneiodonium; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse; D003545:Cysteine; C013461:cysteine sulfinic acid; D000111:Acetylcysteine
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