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Protein-1, and Antioxidant Response Elements Stress-Activated Protein Macrophage Activation by Polycyclic Aromatic Hydrocarbons: Evidence for the Involvement of Stress-Activated Protein Kinases, Activator Protein-1, and Antioxidant Response Elements This information is current as of October 1, 2021. David Ng, Niels Kokot, Timothy Hiura, Mary Faris, Andrew Saxon and Andre Nel J Immunol 1998; 161:942-951; ; http://www.jimmunol.org/content/161/2/942 Downloaded from References This article cites 70 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/161/2/942.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Macrophage Activation by Polycyclic Aromatic Hydrocarbons: Evidence for the Involvement of Stress-Activated Protein Kinases, Activator Protein-1, and Antioxidant Response Elements1 David Ng, Niels Kokot, Timothy Hiura, Mary Faris, Andrew Saxon, and Andre Nel2 Polycyclic aromatic hydrocarbons (PAH) contained in fossil fuel combustion particles enhance the allergic response to common environmental Ags. A key question is: what are molecular pathways in the immune system by which PAH and conversion products drive allergic inflammation? Circumstantial evidence suggests that macrophages are involved in PAH-induced responses. We demonstrate that a representative PAH, b-napthoflavone (BNF), and a representative quinone metabolite, tert-butylhydroxyqui- none (tBHQ), induce Jun kinase and p38 mitogen-activated protein kinase activities in parallel with the generation of activator Downloaded from protein-1 (AP-1) mobility shift complexes in THP-1 and RAW264.7 macrophage cell lines. Activation of mitogen-activated protein kinases was dependent on generation of oxidative stress, and could be inhibited by N-acetylcysteine. Another genetic response pathway linked to PAH is the antioxidant response element (ARE), which regulates expression of detoxifying enzymes. BNF and tBHQ activated a human ARE (hARE) reporter gene in RAW264.7 cells. Interestingly, bacterial lipopolysaccharide also induced hARE/chloramphenicol acetyltransferase activity. While the hARE core, GTGACTCAGC, contains a consensus AP-1 sequence (underlined), AP-1 was not required for hARE activation. This suggests that PAH and their conversion products operate via http://www.jimmunol.org/ ARE-specific transcription factors in the immune system. BNF and tBHQ did, however, induce AP-1 binding to the hARE, while constitutively active Jun kinase interfered in hARE/chloramphenicol acetyltransferase activation. This suggests that AP-1 proteins negatively regulate the hARE. These data establish important activation pathways for PAH in the immune system and provide us with targets to modulate the effect of environmental pollutants on allergic inflammation. The Journal of Immunology, 1998, 161: 942–951. ir pollution is an important public health issue, and a vious studies have directly addressed the effects of such combus- number of pollutants, including suspended particles, car- tion particles and their associated polycyclic aromatic hydrocar- by guest on October 1, 2021 A bon monoxide, lead, nitrogen dioxide, sulfur dioxide, bons (PAH) on the allergic response (6–11). In particular, DEP and ozone, are being monitored by the U.S. Environmental Pro- have been shown to enhance IgE production in humans and ani- tection Agency (1). While ozone and sulfur dioxide have been mals in response to challenge with environmental or experimental studied in some detail, particulate matter is receiving increased allergens (6–11). A key question has become: what are the cellular attention due to accumulating evidence that particles of 10 mmor targets and molecular pathways in the immune system by which less (PM10) can exacerbate respiratory disease, particularly PAH and their conversion products drive allergic inflammation? asthma (2–4). An important component of PM10 is fossil fuel Our nasal challenge studies have shown that DEP alters IgE pro- combustion products, e.g., diesel exhaust particles (DEP)3 (5). Pre- duction both qualitatively and quantitatively. However, the direct effects on B cells occur primarily in cells already committed to IgE production, suggesting involvement of another cell type in the ob- Division of Clinical Immunology and Allergy, Department of Medicine, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095 served in vivo outcomes (8, 11). Similarly, while DEP plus aller- Received for publication December 1, 1997. Accepted for publication March gen challenge increased the in vivo production of Th2 cytokines in 16, 1998. our nasal challenge studies (9), our preliminary data have failed to The costs of publication of this article were defrayed in part by the payment of page show a direct DEP or PAH effect on Th2 cytokine production, charges. This article must therefore be hereby marked advertisement in accordance including activation of the IL-4 and IL-5 promoters in T lympho- with 18 U.S.C. Section 1734 solely to indicate this fact. cytes (not shown). This suggests that a major target for PAH in the 1 This work was supported by U.S. Public Health Service Grant AI-34567 (University of California, Los Angeles, Asthma, Allergy, and Immunologic Disease Center mucosal immune system is a nonlymphoid cell type. funded by National Institute of Allergy and Infectious Diseases and National Institute Macrophages are a PAH target in the respiratory tract for in- on Environmental Health Sciences). haled PAH. It has been demonstrated that a variety of xenobiotics, 2 Address correspondence and reprint requests to Dr. Andre Nel, University of Cal- including PAH, polychlorinated biphenyls, and halogenated aro- ifornia, Los Angeles, School of Medicine, Department of Medicine, CIA, 52-175 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095. E-mail address: matic hydrocarbons, exerts effects on macrophages, including pul- [email protected] monary alveolar macrophages (10, 12–19). These effects include 3 Abbreviations used in this paper: DEP, diesel exhaust particles; Ahr, aromatic hy- induction of oxidative burst activity (10, 12), increased expression drocarbon receptor; AP-1, activator protein-1; ARE, antioxidant response element; of MHC-II gene products (13), induction of cytochrome P4501A1 ATF2, activating transcription factor 2; BNF, b-napthoflavone; CAT, chloramphen- icol acetyltransferase; comp, complex; CYP1A1, cytochrome P4501A1; GST, gluta- (CYP1A1) activity (12, 16, 18), and conversion of benzo(a)pyrene thione S-transferase; hARE, human antioxidant response element; JNK, c-Jun N- terminal kinase; MAPK, mitogen-activated protein kinase; NAC, N-acetylcysteine; NQO1, nicotinamide-adenine dinucleotide phosphate (NADPH):quinone oxidoreduc- oxygen species; tBHQ, tert-butylhydroxyquinone; TCDD, 2,3,7,8-tetrachlorodibenzo- tase; PAH, polycyclic aromatic hydrocarbon; RE, response element; ROS, reactive p-dioxin; XRE, xenobiotic response element. Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 943 of rat and murine phase II enzyme promoters (Fig. 1) (36, 53, 54). One hypothesis is that AP-1 proteins play a role in the activation of the ARE (36, 42, 43, 53, 54). This notion is contentious, how- ever, as some studies have shown that the ARE can be activated independent of AP-1 protein(s) (39–41, 45). Whatever the rela- tionship between ARE and AP-1 proteins, the molecular events leading to the activation of these RE are sensitive biochemical tools to study immune cellular activation by PAH. One of the regulatory pathways for AP-1 proteins are the MAPK cascades that affect transcriptional activation as well as expression of AP-1 FIGURE 1. Base pair sequence of the ARE in different gene promoters, proteins (55). We are particularly interested in the c-Jun N-termi- including reagents used in this work for studying the ARE. The extended nal kinases (JNK), also known as stress-activated protein kinases, ARE in the human NQO1, rat NQO1, and the mouse GST-Ya promoters are and the p38 MAPK cascade because both pathways play a role in shown at the top. The ARE core with an overlapping AP-1 or AP-1-like cellular responses to environmental stress, including exposure to sequence, as well as the upstream AP-1-like elements are shown (under- toxic drugs and chemicals, LPS, inflammatory cytokines, oxidative lined). The hARE sequence, provided by Dr. Anil Jaiswal in the hARE- stress, or hyperosmolarity (55–58). tk-CAT vector, is shown below together with mutant versions of this re- There have been no systematic studies in macrophages of acti- porter gene, designated core mutant (cm) or AP-1 mutant (mAP1). Double- vation of the ARE or the AP-1 pathway by PAH. We sought to stranded oligonucleotides used in gel-shift
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