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Hart and Louise Lyon Laboratory, Division of Clinical Immunology and Allergy, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
Oxidant pollutants such as diesel exhaust particles (DEPs) can initiate and exacerbate airway allergic responses through enhanced IgE production. These effects are especially pronounced in individuals in whom phase II antioxidant enzyme responses are impaired. We confirmed that DEPs and DEP extracts (DEPX) can act directly on B lymphocytes and showed that DEPX could enhance IgH 
germline transcription in a B cell line and in PBMCs. We therefore studied the regulation in B cells of NAD(P)H: quinone oxidoreductase (NQO1) as a typical model phase II enzyme and its role in modulating DEPX-enhanced IgE responses. DEPX increased NQO1 mRNA expression in a dose-dependent manner. NQO1 protein induction by DEPX was confirmed by Western blot. DEPs induced activity of the antioxidant response element located in the NQO1 gene promoter. Induction of both NQO1 mRNA and protein expression could be blocked by coculture with an antioxidant and partly repressed by inhibitors of PI3K and p38 MAPK, but not by inhibitors of MAPK/ERK kinase (MEK/ERK) or protein kinase C. The ability of DEPX to enhance IgE production was blocked by the induction of phase II enzymes, including NQO1 in B cells by the chemical sulforaphane. These findings suggest that a natural protective mechanism in B cells from oxidant pollutants such as diesel particles is the expression of phase II enzymes through induction of antioxidant response elements and support the approach of overexpression of these enzymes as a potential future chemopreventative strategy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant P01 AI050495 and Environmental Protection Agency Grant ES-03-004.
2 Address correspondence and reprint requests to Dr. David Diaz-Sanchez, Division of Clinical Immunology and Allergy, Department of Medicine, UCLA School of Medicine, University of California, Los Angeles, CA 90095. E-mail address: ddiazsa{at}mednet.ucla.edu
3 Abbreviations used in this paper: DEP, diesel exhaust particle; DEPX, DEP extract; ARE, antioxidant response element; Nrf2, NF E2 p45-related factor-2; NAC, N-acetylcysteine; NQO1, NAD(P)H:quinone oxidoreductase 1; ROS, reactive oxygen species; GSTM1, GST µ1; Q-PCR, quantitative PCR; GT, germline transcript.
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