Hindawi Publishing Corporation
Journal of Allergy
Volume 2012, Article ID 372384, 8 pages
Roleof theArylhydrocarbonReceptor(AhR) inthe Pathology of
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
Correspondence should be addressed to Takahito Chiba, firstname.lastname@example.org
Received 17 September 2011; Accepted 18 October 2011
Academic Editor: Brian Oliver
Copyright © 2012 Takahito Chiba et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
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
Both allergic asthma and COPD are defined as airway
inflammatory diseases; however, the inflammatory mech-
anism 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
of several drug-metabolizing enzymes, such as CYP1A1 .
AhR-induced CYP1A1 activation is important for detoxica-
tion. 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
2 Journal of Allergy
In this review article, we summarize current findings
regarding the functional role of AhR molecules in airway
inflammation and focus on bronchial epithelial cells, fibrob-
lasts, granulocytes, and lymphocytes. Understanding the
effects of AhR on these cells would be a breakthrough in our
2.1. Airway Epithelial Cells. Airway epithelial cells are able to
modify allergic airway inflammation by virtue of their ability
such mediator is the moderate bronchial mucin-containing
mucus, which normally protects the airway from exogenous
substances. Hypermucosis in the airway, however, is asso-
ciated 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-
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-
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 arachi-
donic 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
MUC 5AC mRNA
Figure 1: Effects of AhR agonist B[a]Pon MUC5AC mRNA level in
NCI-H292after 12h of incubation. MUC5AC was measured by real-
time RT-PCR. B[a]P induced MUC5AC mRNA expression in dose-
dependent manner. Pretreatment with AhR antagonist, resveratrol,
inhibited AhR-induced MUC5AC upregulation. Data are expressed
as means ± SD (n = 6).
∗∗P < 0.05 versus B[a]P 1μM.
∗P < 0.05 versus control (medium alone).
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 epithe-
lial cells, such as IL-8 and leukotriene B4, may have a chemo-
tactic effect. We previously confirmed that normal human
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
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.
Journal of Allergy3
IL-8 production (pg/mL)
20 nM40 nM 100 nM1 μM 10 μM
Figure 2: Normal human epidermal keratinocytes (NHEKs) were
exposed to B[a]P at various concentrations for 24h, and IL-8
IL-8 production in a dose-dependent manner. Data are expressed as
means ± SD (n = 3).∗P < 0.05 versus control (medium alone).
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 adhe-
sion 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
cytokines and mucus in asthma and COPD, as illustrated in
2.2. Fibroblast or Airway Smooth Muscle. Chronic asthmatic
patients who are unresponsive to treatment experience
progressive and irreversible changes in pulmonary function.
with structural alterations, such as subepithelial fibrosis,
smooth muscle or goblet cell hyperplasia, and airway hyper-
responsiveness . 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
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 . PGE2significantly 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 secre-
tion, 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 con-
firm 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
2.4. Lymphocytes. Allergic asthma is associated with dis-
ruption 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
4 Journal of Allergy
Onset and/or exacerbation
of asthma or COPD
Airway epithelial cells
Figure 3: Schematic diagram of the proposed crosstalk AhR-signaling pathway and inflammatory effects in airway epithelial cells.
3 30 3000
Eotaxin (10 nM)
Eotaxin-stimulated cells (%)
3 30 300
Annexin + PI-cells (%)
with increasing concentrations of troglitazone for 1h. Migration assays were performed using Boyden chambers. Chemotactic response to
eotaxin alone was considered to be 100%, and reactions to lower concentrations are presented relative to eotaxin alone. Data are expressed
as mean ± SD. Troglitazone inhibited the eotaxin-directed eosinophil chemotaxis in a dose-dependent manner (n = 4).
versus eotaxin alone. (b) Effect of troglitazone on eosinophil survival determined by staining with Annexin V-FITC and propidium iodine.
Eosinophils were incubated with and without troglitazone in the presence of 1ng/mL IL-5 for 48h. Eosinophils were treated with Annexin
V to stain early-phase apoptotic cells and with propidium iodine (PI) to stain the late-phase cells. The bar graph shows a dose-dependent
effect of troglitazone on IL-5-induced eosinophil survival (n = 4). Data are expressed as mean ± SD.∗P < 0.05 versus without troglitazone.
∗P < 0.05
Journal of Allergy5
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
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 inflam-
mation, 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 infiltra-
tion. 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.
MUC5AC: Oligomeric mucus/gel forming
BAL: Bronchoalveolar lavage
PPARs:Peroxisome proliferator-activated receptors
PPRE: PPARs response element
IgE: Immunoglobulin E
G-CSF:Granulocyte colony-stimulating factor
FGF:Fibroblast growth factor
EGF:Epidermal growth factor
PDGF:Platelet-derived growth factor.
Chronic obstructive pulmonary disease
Transforming growth factor alpha
AhR nuclear translocator
Dioxin response element
Cytochrome P450 1A1
Reactive oxygen species
Tumor necrosis factor alpha
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
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