Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals.
The proinflammatory effects of particulate pollutants, including diesel exhaust particles (DEP), are related to their content of redox cycling chemicals and their ability to generate oxidative stress in the respiratory tract. An antioxidant defense pathway, which involves phase II enzyme expression, protects against the pro-oxidative and proinflammatory effects of DEP. The expression of enzymes, including heme oxygenase-1 (HO-1) and GST, is dependent on the activity of a genetic antioxidant response element in their promoters. In this study we investigated the mechanism by which redox cycling organic chemicals, prepared from DEP, induce phase II enzyme expression as a protective response. We demonstrate that aromatic and polar DEP fractions, which are enriched in polycyclic aromatic hydrocarbons and quinones, respectively, induce the expression of HO-1, GST, and other phase II enzymes in macrophages and epithelial cells. We show that HO-1 expression is mediated through accumulation of the bZIP transcription factor, Nrf2, in the nucleus, and that Nrf2 gene targeting significantly weakens this response. Nrf2 accumulation and subsequent activation of the antioxidant response element is regulated by the proteasomal degradation of Nrf2. This pathway is sensitive to pro-oxidative and electrophilic DEP chemicals and is also activated by ambient ultrafine particles. We propose that Nrf2-mediated phase II enzyme expression protects against the proinflammatory effects of particulate pollutants in the setting of allergic inflammation and asthma.
Division of Clinical Immunology and Allergy, Department of Medicine, University of California, Los Angeles 90095, USA.
Ning
N
Li
Jawed
J
Alam
M Indira
MI
Venkatesan
Arantza
A
Eiguren-Fernandez
Debra
D
Schmitz
Emma
E
Di Stefano
Ndaisha
N
Slaughter
Erin
E
Killeen
Xiaorong
X
Wang
Aaron
A
Huang
Meiying
M
Wang
Antonio H
AH
Miguel
Arthur
A
Cho
Constantinos
C
Sioutas
Andre E
AE
Nel
D004268:DNA-Binding Proteins / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D005786:Gene Expression Regulation; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D018613:Microscopy, Confocal; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism*; D001335:Vehicle Emissions / Q000009:adverse effects*
D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D015534:Trans-Activators; D001335:Vehicle Emissions; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1