Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
Journal of Allergy 01/2012; 2012:372384. DOI: 10.1155/2012/372384
Source: PubMed


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.

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Available from: Takahito Chiba
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    • "The suspected influence of the dioxin-like PCBs on immunoregulation is, at least partly, thought to be related to interactions with the aryl hydrocarbon receptor (AhR). AhR-mediated responses with dioxin and dioxin-like compounds are thought to contribute to asthma pathogenesis through increased expression of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1 beta, which in turn can induce mucin production, cell chemotaxis, and immunoglobulin E (IgE) production (Chiba et al. 2012). Whether AhR-mediated responses are relevant to effects of developmental exposures to dioxin-like PCBs is unclear. "
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    ABSTRACT: Previous findings suggest that developmental exposures to persistent organochlorine pollutants (POPs) may be detrimental for the development of the immune system in the offspring. Whether these suspected immunoregulatory effects persist beyond early childhood remains unclear. The objective of this study was to evaluate the association between maternal serum concentrations of POPs and the risk of asthma in offspring after 20 years of follow-up. A birth cohort with 965 women was formed in 1988-1989 in Århus, Denmark. Concentrations of six polychlorinated biphenyls (PCBs) (congeners number 118, 138, 153, 156, 170, 180), hexachlorobenzene (HCB), and dichlorodiphenyldichloroethylene (p,p'-DDE) were quantified in maternal serum (n = 872) collected in gestation week 30. Information about offspring use of asthma medications was obtained from the Danish Registry of Medicinal Product Statistics. Maternal serum concentrations of HCB and dioxin-like PCB-118 were positively associated with offspring asthma medication use after 20 years of follow-up (p for trend < 0.05). Compared with subjects in the first tertile of maternal concentration, those in the third tertile of PCB-118 had an adjusted hazard ratio (HR) of 1.90 (95% CI: 1.12, 3.23). For HCB the HR for the third versus the first tertile of maternal concentration was 1.92 (95% CI: 1.15, 3.21). Weak positive associations were also estimated for PCB-156 and the non-dioxin like PCBs (PCB-138, 153, 170, 180). No associations were found for p,p'-DDE. Maternal concentrations of PCB-118 and HCB were associated with increased risk of asthma in offspring followed through 20 years of age.
    Full-text · Article · Oct 2013 · Environmental Health Perspectives
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    • "Tobacco smoke is a remarkable source of polycyclic aromatic hydrocarbons (PAHs) that trigger the AHR signaling pathway [22]–[24], leading to several pathological effects in humans through AHR-dependent changes in gene expression [25]–[28]. AHRR is a known tumor suppressor, mediating detoxification of PAHs, which are the principle carcinogenic agents causing tobacco-related lung and other cancers [29]. Recently a differential methylation of CpG sites in smokers within the AHRR gene has been demonstrated in lymphoblasts and pulmonary macrophages by Monick et al. [12]. "
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    ABSTRACT: Environmental factors such as tobacco smoking may have long-lasting effects on DNA methylation patterns, which might lead to changes in gene expression and in a broader context to the development or progression of various diseases. We conducted an epigenome-wide association study (EWAs) comparing current, former and never smokers from 1793 participants of the population-based KORA F4 panel, with replication in 479 participants from the KORA F3 panel, carried out by the 450K BeadChip with genomic DNA obtained from whole blood. We observed wide-spread differences in the degree of site-specific methylation (with p-values ranging from 9.31E-08 to 2.54E-182) as a function of tobacco smoking in each of the 22 autosomes, with the percent of variance explained by smoking ranging from 1.31 to 41.02. Depending on cessation time and pack-years, methylation levels in former smokers were found to be close to the ones seen in never smokers. In addition, methylation-specific protein binding patterns were observed for cg05575921 within AHRR, which had the highest level of detectable changes in DNA methylation associated with tobacco smoking (-24.40% methylation; p = 2.54E-182), suggesting a regulatory role for gene expression. The results of our study confirm the broad effect of tobacco smoking on the human organism, but also show that quitting tobacco smoking presumably allows regaining the DNA methylation state of never smokers.
    Full-text · Article · May 2013 · PLoS ONE
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    • "In summary, cells expressing functional IDO or TDO may modulate local immune effector functions by stimulating AhR in innate and adaptive immune cells, such as T cells, Th17, Tregs, and DCs, which reinforces IDO-mediated regulatory phenotypes in these cells. AhR expressed on non-immune cells including lung epithelial cells, liver hepatocytes, and endothelial cells may also mediate cell responses in tissue development, physiological function, and immune responses (Walisser et al., 2005; Chiba et al., 2011, 2012), indicating ubiquitous influences of tryptophan metabolites on both hematopoietic and non-hematopoietic cells. The relative importance of the immune modulatory effects of IDO-mediated tryptophan withdrawal to trigger the ISR in immune cells and production of tryptophan catabolites is not known. "
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    ABSTRACT: The term "immune privilege" was coined to describe weak immunogenicity (hypo-immunity) that manifests in some transplant settings. We extended this concept to encompass hypo-immunity that manifests at local sites of inflammation relevant to clinical diseases. Here, we focus on emerging evidence that enhanced tryptophan catabolism is a key metabolic process that promotes and sustains induced immune privilege, and discuss the implications for exploiting this knowledge to improve treatments for hypo-immune and hyper-immune syndromes using strategies to manipulate tryptophan metabolism.
    Full-text · Article · May 2012 · Frontiers in Immunology
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