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Journal of Allergy
Volume 2012 (2012), Article ID 372384, 8 pages
Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD
1Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
2Department of Clinical and Laboratory Medicine, Akita University School of Medicine, Akila 010-8502, Japan
3Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan
Received 17 September 2011; Accepted 18 October 2011
Academic Editor: Brian Oliver
Copyright © 2012 Takahito Chiba et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.
Both allergic asthma and COPD are defined as airway inflammatory diseases; however, the inflammatory mechanism is different for each disease. Nocuous agents such as PCBs, B[a]P, and dioxin-like compounds in cigarette smoke and environmental pollutants have the potential to induce inflammation or exacerbate chronic bronchitis, asthma, COPD, and lung cancer [1–4]. In addition to airway epithelial cells, many inflammatory cells, including Th2 cells, eosinophils, and basophils, play a major pathophysiological role in asthma and COPD [5–8]. Cigarette smoke and environmental pollutants activate these inflammatory cells, and they contribute to the activation of growth factors and cytokines. For example, exposure to some types of noxious agents increases the rate of TGF-α, TGF-β, IL-1β, IL-6, IL-8, and IFN-γ gene expression [9–12]. While the molecular signaling mechanism for this transcriptional modulation of cytokines remains to be determined, it has been recently recognized that these effects are mainly mediated through the binding of noxious agents to the AhR. All major human cell types express AhR, including pulmonary tissue [13, 14]. The liver, adipose tissue, and skin are the major storage sites of AhR ligands in humans . These AhR ligands are also concentrated in bronchial epithelial cells, suggesting that the respiratory system is sensitive to AhR ligands .
The AhR is a ligand-activated transcription factor, and after ligation of dioxins to the AhR, the receptor translocates from the cytosol to the nucleus, where it heterodimerizes with the ARNT. It then binds to a DRE, an enhancer sequence of several drug-metabolizing enzymes, such as CYP1A1 . AhR-induced CYP1A1 activation is important for detoxication. CYPs convert B[a]P and dioxin-like compounds into physiologic metabolites that exert effects on cell growth, differentiation, and migration. A number of researchers have demonstrated the molecular aspects of the AhR pathway by using selective agonists such as TCDD or B[a]P among PAHs.
In this review article, we summarize current findings regarding the functional role of AhR molecules in airway inflammation and focus on bronchial epithelial cells, fibroblasts, granulocytes, and lymphocytes. Understanding the effects of AhR on these cells would be a breakthrough in our understanding of the pathology and treatment of asthma and COPD.
2. Airway Inflammatory Effect through AhR Activation in Asthma and COPD
2.1. Airway Epithelial Cells
Airway epithelial cells are able to modify allergic airway inflammation by virtue of their ability to produce a variety of inflammatory mediators [18, 19]. One such mediator is the moderate bronchial mucin-containing mucus, which normally protects the airway from exogenous substances. Hypermucosis in the airway, however, is associated with several respiratory diseases, including asthma and COPD. Mucus hypersecretion in the airway increases coughing and expectoration of sputum. Clara cells in the airway can secrete a wide variety of glycoproteins, such as mucins and SP-D, and are very sensitive to AhR stimulation [20, 21]. Wong et al. recently have reported TCDD, an AhR agonist, increased expression of inflammatory cytokines, MUC5AC, and MMPs via AhR signaling in a Clara-cell-derived cell line . Mucus production is typically mediated by cytokine or lipid mediator release, or an increase of ROS [22–24]. Studies using AhR agonists and inhibitors have demonstrated that AhR activation induces the production of cytokines such as TGF-α, TNF-α, and MMP through receptors in human hematocytes and epithelial cells [21, 25–27]. Wong et al. also reported an increase of COX-2 and IL-1β mRNA expression in response to AhR activation . The production of prostanoids such as PGE2, which is derived from COX-2, can activate mucin production in the airway . Although prostaglandins derived from COX-2 pathway activation may be responsible for AhR-induced mucin production in the bronchial epithelial cells, the mechanism of their action remains to be determined. Therefore, it is of paramount interest to investigate the mechanism by which AhR activation induces mucin production. In an earlier study, we reported findings similar to those by Wong et al. In our study, we found that AhR activation upregulates the expression of MUC5AC and mucin secretion in a NCI-H292 cell line that was derived from a bronchiolar Clara cell  (Figure 1). Moreover, we concurrently showed that AhR activation induced ROS generation, and the antioxidant agent NAC inhibited B[a]P-induced MUC5AC upregulation. Kopf and Walker also demonstrated that TCDD-induced AhR activation increased ROS levels in endothelial cells . Another prostaglandin, PGD2, is synthesized from arachidonic acid via the catalytic activities of COX in epithelial cells and mast cells. It is released into the airway following an antigen challenge during an acute allergic response . PGD2 induces chemotaxis of Th2 cells, eosinophils, and basophils as a consequence of the activation of its receptors . This suggests that PGD2 promotes inflammation in allergic asthma. Prostaglandins that are derived from COX-2 pathway activation and ROS that are induced by AhR activation are the major inflammatory mediators capable of inducing mucin production, inflammatory cell chemotaxis, or inflammatory cell activation. Therefore, increased levels of prostaglandins and ROS, either directly or through the formation of lipid peroxidation products, may enhance the inflammatory response in both asthma and COPD.
Neutrophils isolated from peripheral blood and BAL fluid of asthmatic patients generate more ROS than cells from normal patients. Additionally, the production of ROS correlates with the degree of airway hyperresponsiveness [32, 33]. Neutrophils and macrophages are also known to migrate into the lungs of COPD patients [34, 35]. Indeed, the neutrophils that mediate ROS-induced injury to the airway epithelium are responsible for hyperresponsiveness in human peripheral airways, suggesting that neutrophils play an important role in the pathogenesis of asthma and COPD . AhR-derived inflammatory mediators in airway epithelial cells, such as IL-8 and leukotriene B4, may have a chemotactic effect. We previously confirmed that normal human epidermal keratinocytes (NHEKs) enhanced IL-8 production through AhR activation  (Figure 2). Martinez et al. demonstrated that IL-8 gene expression was upregulated by TCDD in A549 cells from a bronchial epithelial cell line . However, they could not detect IL-8 production at the protein level in airway epithelial cells. We were also unable to detect IL-8 production from AhR-activation in NCI-H292 cells using ELISA analysis (data not shown). Although it is not clear that AhR directly modulates NF-κB, the induction of a transcription factor for IL-8, tumor necrosis factor, or IL-1β by AhR activation might impact IL-8 production in airway epithelial cells [21, 25, 26, 39].
Cell-cell contact molecules in the airways create a barrier that plays an important role in the defense against bacteria. Loss of expression of cell-cell contact molecules, such as E-cadherin, reduces the ability of epithelial cells to function as a barrier and may increase the allergic response and susceptibility to infection. Indeed, E-cadherin and α-catenin interacted with cytosolic domain of the cadherin expression are significantly lower in asthmatic than in nonasthmatic subjects . AhR also regulates the expression of adhesion molecules and consequently controls cell-cell contact. Exposure to TCDD from a human breast cancer cell line downregulates E-cadherin expression . Using rat liver epithelial cells, Dietrich et al. demonstrated that TCDD exposure inhibits the expression of γ-catenin, which links E-cadherin to actin filaments . We hypothesize that several pathways may be involved in the production of inflammatory cytokines and mucus in asthma and COPD, as illustrated in Figure 3.
2.2. Fibroblast or Airway Smooth Muscle
Chronic asthmatic patients who are unresponsive to treatment experience progressive and irreversible changes in pulmonary function. These changes, known as “airway remodeling,” are associated with structural alterations, such as subepithelial fibrosis, smooth muscle or goblet cell hyperplasia, and airway hyperresponsiveness . In chronic asthma patients, fibrosis is due to increased deposition of extracellular matrix. Increases in airway smooth muscle mass are thought to be caused by faster proliferation, mitogenic, or inflammatory stimuli . Some of the factors contributing to these effects are TGF, FGF, EGF, and PDGF. TGF-β is one of these contributors and is a major effector cytokine that can increase deposition by fibroblasts and airway smooth muscle hypertrophy. Guo et al. reported that levels of RNA for TGF-β2 and TGF-β2-related genes increased in AhR-knockout smooth muscle cells . This suggests that AhR may repress the TGF-β- signaling pathway, resulting in an anti-inflammatory effect unlike in rodent lung cells. On the other hand, cigarette smoke, via AhR, can induce cyclooxygenase and PGE2 in human lung fibroblasts . PGE2 significantly enhances cigarette smoke extract-treated neutrophil chemotaxis and adhesion to airway epithelial cells . In fact, the concentration of PGE2 in the sputum of COPD patients is correlated with the number of infiltrating neutrophils . Neutrophil activation through AhR signaling plays a causal role in pathogenesis and exacerbation of COPD.
2.3. Granulocytes with Focus on Eosinophils
Eosinophils play an essential role in the pathology of asthma because they contribute to tissue injury, vascular leakage, mucus secretion, and tissue remodeling by releasing cytotoxic granule proteins, ROS, and lipid mediators . Because eosinophils are the final effector cells in allergic inflammation, it is important to study the process by which nuclear receptors, such as AhR, activate eosinophils in order to understand the pathogenesis of allergic diseases. For example, PPARs are among the important ligand-activated transcription factors that regulate the expression of genes involved in many cellular functions, including differentiation, immune responses, and inflammation [49, 50]. The PPAR subfamily consists of 3 isotypes: PPARα, PPARβ/δ, and PPARγ, all of which have been identified in eosinophils. These nuclear receptors form heterodimers with retinoid X receptors, bind to a specific DNA sequence (PPRE), and activate target gene transcription. In vivo and in vitro evidence suggests that PPARα and PPARγ expression in granulocytes and dendritic cells plays a critical role as an inflammatory suppressive regulator in allergic diseases. Treatment with the PPARγ agonist, rosiglitazone, decreases the clinical severity of skin lesions in atopic dermatitis and airway inflammation in asthmatic patients [51, 52]. We previously demonstrated that the PPARγ agonist troglitazone reduced IL-5-stimulated eosinophil survival, eotaxin-directed eosinophil chemotaxis, and functional augmentation of eosinophil adhesion in a concentration-dependent manner. These changes occurred without reducing the quantitative expression of β2 integrins [53, 54] (Figure 4). It has been lately shown that PPARγ induction is suppressed during the activation of the AhR by TCDD . In addition, Cho et al. demonstrated that CYP1B1 upregulation induced the inhibition of AhR expression in 10T1/2 cells derived from preadipocyte lines. Moreover, the reduced AhR expression was accompanied by an increase in PPARγ expression . These results suggest that the AhR signal may repress migration, degranulation, and cellular adhesion of eosinophils. This may impair the antiallergic effects induced by PPARγ. We were able to confirm AhR expression in human eosinophils using RT-PCR (data not shown). Clarification of the interaction between AhR and PPARγ signals should broaden our understanding not only of the functional role of eosinophils but also of asthma regulation.
Allergic asthma is associated with disruption of the immune system, particularly an imbalance of Th1 and Th2 cells. It is well known that Th2 cells play a key role in the regulation of inflammatory reactions through the release of Th2 cytokines. AhR is known to exert an influence on allergic immunoregulation. In fact, Tauchi et al. reported that mice with constitutive AhR activation developed severe skin lesions that were similar to the lesions seen in atopic dermatitis. The lesions were accompanied by high serum levels of IgE and increased production of IL-4 and IL-5 from stimulated splenic lymphocytes . In addition, AhR expression in splenic B cells was enhanced by the presence of lipopolysaccharide, which is known to exacerbate asthma and COPD . PAH and TCDD increase IgE production in cocultures with purified B cells . These results provide further evidence that AhR may play a complex role in the humoral immunological balance in airway allergic pathogenesis.
Th17 cells have been recently classified as a subtype of helper T cells that are characterized by the production of IL-17 . AhR activation promotes the development of Th17 cells and results in increased pathology in animal models of multiple sclerosis . Th17 cells found in the skin, gastrointestinal tract, and bronchial tubes are involved in inflammatory conditions, such as inflammatory bowel disease and asthma . The IL-17 produced by Th17 cells is a potent activator of NF-κB, thereby, increasing the levels of inflammatory cytokines such as IL-8, IL-6, TNF-α, G-CSF, and GM-CSF . Therefore, although Th17 plays a role in regulating neutrophil and macrophage inflammation, it is not known whether IL-17 induced by AhR activation contributes to the development of asthma or COPD. Clinically, IL-17 levels in BAL fluid, sputum, and peripheral blood from patients with allergic asthma are higher than those in healthy controls [64, 65]. A knockout mouse model of the IL-17 receptor showed reduced OVA-induced airway hyperresponsiveness and eosinophil infiltration. Additionally, the levels of IgE and Th2 cytokines in knockout mice were not as highly elevated as they were in wild-type mice . Furthermore, stimulation with IL-17 increased the concentration of biologically active MMP-9 in mouse airways. IL-17 protein, as represented by neutrophilic inflammation, has been detected in COPD patients, but at a lower level than observed in asthma patients . Human lymphocytes, however, may behave differently. For example, AhR agonists appear to favor IL-22 but not IL-17 production in humans . These studies suggest a role of AhR-induced Th17 in promoting allergic or inflammatory airway diseases, but there are interesting differences between human and mouse T cells. These differences suggest that the response to AhR activation may vary according to cell type, maturation, and differentiation process.
We reviewed studies on the relationship between AhR function and airway inflammation, as it is important in the initial phase of asthma/COPD. In addition to studying the toxicological effects, we wish to promote studies focused on the immune regulation of endogenous AhR pathways. Moreover, it seems increasingly apparent that AhR acts by competing with other nuclear receptors in a complex manner. Further investigation may yield a novel treatment strategy for AhR-associated lung diseases.
|COPD:||Chronic obstructive pulmonary disease|
|TGF-α:||Transforming growth factor alpha|
|ARNT:||AhR nuclear translocator|
|DRE:||Dioxin response element|
|CYP1A1:||Cytochrome P450 1A1|
|ROS:||Reactive oxygen species|
|TNF-α:||Tumor necrosis factor alpha|
|MUC5AC:||Oligomeric mucus/gel forming|
|PPARs:||Peroxisome proliferator-activated receptors|
|PPRE:||PPARs response element|
|G-CSF:||Granulocyte colony-stimulating factor|
|FGF:||Fibroblast growth factor|
|EGF:||Epidermal growth factor|
|PDGF:||Platelet-derived growth factor.|
This work was supported by the Environment Technology Development Fund of the Ministry of the Environment of Japan and in part by the Ministry of Health, Labour, and Welfare of Japan.
- T. K. Baginski, K. Dabbagh, C. Satjawatcharaphong, and D. C. Swinney, “Cigarette smoke synergistically enhances respiratory mucin induction by proinflammatory stimuli,” American Journal of Respiratory Cell and Molecular Biology, vol. 35, no. 2, pp. 165–174, 2006.
- N. B. Marshall and N. I. Kerkvliet, “Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells,” Annals of the New York Academy of Sciences, vol. 1183, pp. 25–37, 2010.
- D. R. Patel and D. N. Homnick, “Pulmonary effects of smoking,” Adolescent Medicine, vol. 11, no. 3, pp. 567–576, 2000.
- American Thoracic Society, “Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma,” American Review of Respiratory Diseases, vol. 136, pp. 225–243, 1987.
- H. Lai and D. F. Rogers, “New pharmacotherapy for airway mucus hypersecretion in asthma and COPD: targeting intracellular signaling pathways,” Journal of Aerosol Medicine and Pulmonary Drug Delivery, vol. 23, no. 4, pp. 219–231, 2010.
- P. J. Barnes, “Immunology of asthma and chronic obstructive pulmonary disease,” Nature Reviews Immunology, vol. 8, no. 3, pp. 183–192, 2008.
- T. Mauad and M. Dolhnikoff, “Pathologic similarities and differences between asthma and chronic obstructive pulmonary disease,” Current Opinion in Pulmonary Medicine, vol. 14, no. 1, pp. 31–38, 2008.
- M. N. Hylkema, P. J. Sterk, W. I. de Boer, and D. S. Postma, “Tobacco use in relation to COPD and asthma,” European Respiratory Journal, vol. 29, no. 3, pp. 438–445, 2007.
- Z. W. Lai, C. Hundeiker, E. Gleichmann, and C. Esser, “Cytokine gene expression during ontogeny in murine thymus on activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin,” Molecular Pharmacology, vol. 52, no. 1, pp. 30–37, 1997.
- C. Vogel and J. Abel, “Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on growth factor expression in the human breast cancer cell line MCF-7,” Archives of Toxicology, vol. 69, no. 4, pp. 259–265, 1995.
- C. Vogel, S. Donat, O. Döhr et al., “Effect of subchronic 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on immune system and target gene responses in mice: calculation of benchmark doses for CYP1A1 and CYPIA2 related enzyme activities,” Archives of Toxicology, vol. 71, no. 6, pp. 372–382, 1997.
- T. K. Warren, K. A. Mitchell, and B. P. Lawrence, “Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses the humoral and cell-mediated immune responses to influenza A virus without affecting cytolytic activity in the lung,” Toxicological Sciences, vol. 56, no. 1, pp. 114–123, 2000.
- M. Ema, N. Matsushita, K. Sogawa et al., “Human arylhydrocarbon receptor: functional expression and chromosomal assignment to 7p21,” Journal of Biochemistry, vol. 116, no. 4, pp. 845–851, 1994.
- T. Chiba, H. Uchi, G. Tsuji, H. Gondo, Y. Moroi, and M. Furue, “Arylhydrocarbon receptor (AhR) activation in airway epithelial cells induces MUC5AC via reactive oxygen species (ROS) production,” Pulmonary Pharmacology and Therapeutics, vol. 24, pp. 133–140, 2011.
- M. Van den Berg, J. De Jongh, H. Poiger, and J. R. Olson, “The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity,” Critical Reviews in Toxicology, vol. 24, no. 1, pp. 1–74, 1994.
- K. Alexandrov, M. Rojas, and S. Satarug, “The critical DNA damage by benzo(a)pyrene in lung tissues of smokers and approaches to preventing its formation,” Toxicology Letters, vol. 198, no. 1, pp. 63–68, 2010.
- J. Mimura and Y. Fujii-Kuriyama, “Functional role of AhR in the expression of toxic effects by TCDD,” Biochimica et Biophysica Acta, vol. 1619, no. 3, pp. 263–268, 2003.
- J. H. Wang, C. J. Trigg, J. L. Devalia, S. Jordan, and R. J. Davies, “Effect of inhaled beclomethasone dipropionate on expression of proinflammatory cytokines and activated eosinophils in the bronchial epithelium of patients with mild asthma,” Journal of Allergy and Clinical Immunology, vol. 94, no. 6 I, pp. 1025–1034, 1994.
- S. Ying, Q. Meng, K. Zeibecoglou et al., “Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (intrinsic) asthmatics,” Journal of Immunology, vol. 163, no. 11, pp. 6321–6329, 1999.
- A. M. Tritscher, J. Mahler, C. J. Portier, G. W. Lucier, and N. J. Walker, “Induction of lung lesions in female rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin,” Toxicologic Pathology, vol. 28, no. 6, pp. 761–769, 2000.
- P. S. Wong, C. F. Vogel, K. Kokosinski, and F. Matsumura, “Arylhydrocarbon receptor activation in NCI-H441 cells and C57BL/6 mice: possible mechanisms for lung dysfunction,” American Journal of Respiratory Cell and Molecular Biology, vol. 42, no. 2, pp. 210–217, 2010.
- K. E. White, Q. Ding, B. B. Moore et al., “Prostaglandin E2 mediates IL-1β-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors,” Journal of Immunology, vol. 180, no. 1, pp. 637–646, 2008.
- J. M. Lora, D. M. Zhang, S. M. Liao et al., “Tumor necrosis factor-alpha triggers mucus production in airway epithelium through an IkappaB kinase beta-dependent mechanism,” Journal of Biological Chemistry, vol. 280, no. 43, pp. 36510–36517, 2005.
- M. Perrais, P. Pigny, M. C. Copin, J. P. Aubert, and I. Van Seuningen, “Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1,” Journal of Biological Chemistry, vol. 277, no. 35, pp. 32258–32267, 2002.
- H. Cheon, Y. S. Woo, J. Y. Lee et al., “Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages,” Experimental and Molecular Medicine, vol. 39, no. 4, pp. 524–534, 2007.
- J. W. Davis Jr., A. D. Burdick, F. T. Lauer, and S. W. Burchiel, “The aryl hydrocarbon receptor antagonist, methoxy- nitroflavone, attenuates 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent regulation of growth factor signaling and apoptosis in the MCF-10A cell line,” Toxicology and Applied Pharmacology, vol. 188, no. 1, pp. 42–49, 2003.
- M. Ishida, S. Mikami, E. Kikuchi et al., “Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer,” Carcinogenesis, vol. 31, no. 2, Article ID bgp222, pp. 287–295, 2010.
- K. E. White, Q. Ding, B. B. Moore et al., “Prostaglandin E2 mediates IL-1β-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors,” Journal of Immunology, vol. 180, no. 1, pp. 637–646, 2008.
- P. G. Kopf and M. K. Walker, “2,3,7,8-tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A1,” Toxicology and Applied Pharmacology, vol. 245, no. 1, pp. 91–99, 2010.
- J. J. Murray, A. B. Tonnel, A. R. Brash et al., “Release of prostaglandin D 2 into human airways during acute antigen challenge,” The New England Journal of Medicine, vol. 315, pp. 800–804, 1986.
- T. Chiba, A. Kanda, S. Ueki et al., “Possible novel receptor for PGD2 on human bronchial epithelial cells,” International Archives of Allergy and Immunology, vol. 143, supplement 1, pp. 23–27, 2007.
- J. Seltzer, B. G. Bigby, M. Stulbarg et al., “O3-induced change in bronchial reactivity to methacholine and airway inflammation in humans,” Journal of Applied Physiology, vol. 60, pp. 1321–1326, 1986.
- T. J. N. Hiltermann, E. A. Peters, B. Alberts et al., “Ozone-induced airway hyperresponsiveness in patients with asthma: role of neutrophil-derived serine proteinases,” Free Radical Biology and Medicine, vol. 24, no. 6, pp. 952–958, 1998.
- M. Saetta, G. Turato, P. Maestrelli, C. E. Mapp, and L. M. Fabbri, “Cellular and structural bases of chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 163, no. 6, pp. 1304–1309, 2001.
- P. J. Barnes, “Mediators of chronic obstructive pulmonary disease,” Cell and Molecular Biology, vol. 50, pp. OL627–OL637, 2004.
- P. Kirkham and I. Rahman, “Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy,” Pharmacology and Therapeutics, vol. 111, no. 2, pp. 476–479, 2006.
- G. Tsuji, M. Takahara, H. Uchi et al., “An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway,” Journal of Dermatological Science, vol. 62, pp. 42–49, 2011.
- J. M. Martinez, C. A. Afshari, P. R. Bushel, A. Masuda, T. Takahashi, and N. J. Walker, “Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells,” Toxicological Sciences, vol. 69, no. 2, pp. 409–423, 2002.
- T. J. Standiford, S. L. Kunkel, M. A. Basha et al., “Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung,” Journal of Clinical Investigation, vol. 86, no. 6, pp. 1945–1953, 1990.
- W. I. de Boer, H. S. Sharma, S. M. Baelemans, H. C. Hooqsteden, B. N. Lambrecht, and G. J. Braunstahl, “Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation,” Canadian Journal of Physiology and Pharmacology, vol. 86, pp. 105–112, 2008.
- L. L. Collins, B. J. Lew, and B. P. Lawrence, “TCDD exposure disrupts mammary epithelial cell differentiation and function,” Reproductive Toxicology, vol. 28, no. 1, pp. 11–17, 2009.
- C. Dietrich, D. Faust, M. Moskwa, A. Kunz, K. W. Bock, and F. Oesch, “TCDD-dependent downregulation of gamma-catenin in rat liver epithelial cells (WB-F344),” International Journal of Cancer, vol. 103, no. 4, pp. 435–439, 2003.
- W. Busse, J. Elias, D. Sheppard, and S. Banks-Schlegel, “Airway remodeling and repair,” American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 3, pp. 1035–1042, 1999.
- Y. Sumi and Q. Hamid, “Airway remodeling in asthma,” Allergology International, vol. 56, no. 4, pp. 341–348, 2007.
- J. Guo, M. Sartor, S. Karyala et al., “Expression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice,” Toxicology and Applied Pharmacology, vol. 194, no. 1, pp. 79–89, 2004.
- C. A. Martey, C. J. Baglole, T. A. Gasiewicz, P. J. Sime, and R. P. Phipps, “The aryl hydrocarbon receptor is a regulator of cigarette smoke induction of the cyclooxygenase and prostaglandin pathways in human lung fibroblasts,” American Journal of Physiology, vol. 289, no. 3, pp. L391–L399, 2005.
- M. Profita, A. Sala, A. Bonanno et al., “Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke and cyclooxygenase products,” American Journal of Physiology, vol. 298, no. 2, pp. 261–269, 2010.
- H. Kita, C. R. Adolphason, and G. J. Gleich, “Biology of eosinophils,” in Middleton’s Allergy: Principles and Practice, N. F. Anderson, J. W. Yunginger, W. W. Busse, B. S. Bochner, S. T. Holgate, and F. E. Simons, Eds., pp. 305–332, Mosby, Philadelphia, Pa, USA, 2003.
- I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990.
- S. A. Kliewer, J. M. Lehmann, and T. M. Willson, “Orphan nuclear receptors: shifting endocrinology into reverse,” Science, vol. 284, no. 5415, pp. 757–760, 1999.
- R. Behshad, K. D. Cooper, and N. J. Korman, “A retrospective case series review of the peroxisome proliferator-activated receptor ligand rosiglitazone in the treatment of atopic dermatitis,” Archives of Dermatology, vol. 144, no. 1, pp. 84–88, 2008.
- M. Spears, I. Donnelly, L. Jolly et al., “Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma,” Clinical Pharmacology and Therapeutics, vol. 86, no. 1, pp. 49–53, 2009.
- S. Ueki, T. Adachi, J. Bourdeaux et al., “Expression of PPARgamma in eosinophils and its functional role in survival and chemotaxis,” Immunology Letters, vol. 86, no. 2, pp. 183–189, 2003.
- H. Hirasawa, T. Chiba, S. Ueki et al., “The synthetic PPARgamma agonist troglitazone inhibits eotaxin-enhanced eosinophil adhesion to ICAM-1-coated plates,” International archives of allergy and immunology, vol. 146, supplement 1, pp. 11–15, 2008.
- P. R. Hanlon, L. G. Ganem, Y. C. Cho, M. Yamamoto, and C. R. Jefcoate, “AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-gamma1 expression and subsequent adipocyte differentiation,” Toxicology and Applied Pharmacology, vol. 189, no. 1, pp. 11–27, 2003.
- Y. C. Cho, W. Zheng, M. Yamamoto, X. Liu, P. R. Hanlon, and C. R. Jefcoate, “Differentiation of pluripotent C3H10T1/2 cells rapidly elevates CYP1B1 through a novel process that overcomes a loss of Ah receptor,” Archives of Biochemistry and Biophysics, vol. 439, no. 2, pp. 139–153, 2005.
- M. Tauchi, A. Hida, T. Negishi et al., “Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions,” Molecular and Cellular Biology, vol. 25, no. 21, pp. 9360–9368, 2005.
- R. S. Marcus, M. P. Holsapple, and N. E. Kaminski, “Lipopolysaccharide activation of murine splenocytes and splenic B cells increased the expression of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator,” Journal of Pharmacology and Experimental Therapeutics, vol. 287, pp. 1113–1118, 1998.
- H. Takenaka, K. Zhang, D. Diaz-Sanchez, A. Tsien, and A. Saxon, “Enhanced human IgE production results from exposure to the aromatic hydrocarbons from diesel exhaust: direct effects on B-cell IgE production,” Journal of Allergy and Clinical Immunology, vol. 95, no. 1, pp. 103–115, 1995.
- E. Bettelli, T. Korn, M. Oukka, and V. K. Kuchroo, “Induction and effector functions of T(H)17 cells,” Nature, vol. 453, no. 7198, pp. 1051–1057, 2008.
- F. J. Quintana, A. S. Basso, A. H. Iglesias et al., “Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor,” Nature, vol. 453, no. 7191, pp. 65–71, 2008.
- L. A. Tesmer, S. K. Lundy, S. Sarkar, and D. A. Fox, “Th17 cells in human disease,” Immunological Reviews, vol. 223, no. 1, pp. 87–113, 2008.
- S. L. Gaffen, “An overview of IL-17 function and signaling,” Cytokine, vol. 43, no. 3, pp. 402–407, 2008.
- K. Oboki, T. Ohno, H. Saito, and S. Nakae, “Th17 and allergy,” Allergology International, vol. 57, no. 2, pp. 121–134, 2008.
- J. F. Alcorn, C. R. Crowe, and J. K. Kolls, “TH17 cells in asthma and COPD,” Annual Review of Physiology, vol. 72, pp. 495–516, 2009.
- S. Schnyder-Candrian, D. Togbe, I. Couillin et al., “Interleukin-17 is a negative regulator of established allergic asthma,” Journal of Experimental Medicine, vol. 203, no. 12, pp. 2715–2725, 2006.
- O. Prause, S. Bozinovski, G. P. Anderson, and A. Lindén, “Increased matrix metalloproteinase-9 concentration and activity after stimulation with interleukin-17 in mouse airways,” Thorax, vol. 59, no. 4, pp. 313–317, 2004.
- J. M. Ramirez, N. C. Brembilla, O. Sorg et al., “Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells,” European Journal of Immunology, vol. 40, no. 9, pp. 2450–2459, 2010.