Abstract
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.
Highlights
NOVEMBER 5, 2010 VOLUME 285 NUMBER 45 tion against oxidative stress [1,2,3]
Chemical antioxidants, Nox inhibitor, and Nox2 deficiency decreased LPS-mediated Srx induction as well as ROS production, suggesting that Nox2-derived ROS may contribute to regulation of Srx induction in macrophages exposed to LPS
LPS-mediated Srx induction was blocked by pretreatment with both cycloheximide and actinomycin D, suggesting that LPSmediated Srx induction was regulated on the transcriptional level (Fig. 1D)
Summary
NOVEMBER 5, 2010 VOLUME 285 NUMBER 45 tion against oxidative stress [1,2,3]. There are six mammalian Prx isoforms, which are distributed in most cellular compartments, including cytosol, mitochondria, nucleus, endoplasmic reticulum, and peroxisomes. In primary mouse BMM cells, Srx expression was increased by LPS treatment at the protein and the mRNA levels (Fig. 1, G and H).
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