Semin Immunopathol (2013) 35:677–691
DOI 10.1007/s00281-013-0394-4
REVIEW
Functions of the aryl hydrocarbon receptor in the skin
Charlotte Esser & Imke Bargen & Heike Weighardt &
Thomas Haarmann-Stemmann & Jean Krutmann
Received: 21 January 2013 / Accepted: 16 July 2013 / Published online: 16 August 2013
# Springer-Verlag Berlin Heidelberg 2013
Abstract Among other functions, the skin serves as the
barrier against the environment and provides vital pro-
tection from physical or chemical harm and from in-
fection. Skin cells express the aryl hydrocarbon recep-
tor (AHR), a ligand-activated transcription factor and
sensor of environmental chemicals; at the same time,
AHR ligands are abundant in skin from exogenous or
endogenous sources. For example, solar radiation, in
particular ultraviolet (UV) B, generates AHR ligands
from tryptophan in the skin. Recent evidence has
shown that AHR is involved in the (patho)physiology
of skin including the regulation of skin pigmentation,
photocarcinogenesis, and skin inflammation. We here
provide a state-of-the-art summary of work which re-
lates to the role of the AHR in (1) adaptive responses
against environmental challenges such as UVB or top-
ical chemicals and (2) intrinsic developmental roles for
homeostasis of skin cells and (3) skin immunity. We
also discuss the existing evidence that AHR antagonists
or AHR ligands may be used for the prevention and/or
treatment of skin disease.
Keywords Aryl hydrocarbon receptor . Epidermis .
Langerhans cells . Psoriasis . Skin cancer . Pigmentation .
FICZ . UV
This article is a contribution to the special issue on Roles of Aryl
Hydrocarbon Receptor in Controlling Immunity - Guest Editors: C. Pot,
V. Kuchroo, and F. Quintaña
C. Esser (*) : I. Bargen : H. Weighardt : T. Haarmann-Stemmann :
J. Krutmann
Leibniz-Research Institute for Environmental Medicine (IUF),
Auf’m Hennekamp 50, 40225 Dusseldorf, Germany
e-mail: chesser@uni-duesseldorf.de
Background
The skin covers the whole body and is in constant contact with
environmental factors, such as heat and cold, sunlight, any
chemicals one touches or applies, bacteria, viruses, etc. The
skin is uniquely suited to this task, and forms an effective
barrier against environmental harm, while protecting the in-
tegrity of the body.
Integration of endogenous and exogenous signals is a
challenge for all cells and organs. Receptors, which can sense
environmental signals and physiological/metabolic imbal-
ances, trigger intracellular events cumulating in transcription,
protein expression, and cellular change. The areas of the body,
which are in direct contact with the environment, are endowed
with special cells and mechanisms for the response to envi-
ronmental situations. A major sensor of chemical signals is the
aryl hydrocarbon receptor (AHR), a member of the evolution-
arily old family of per-arnt-sim basic helix-loop-helix tran-
scription factors (PAS-bHLH). Similar to the steroid and
glucocorticoid hormones, AHR resides in the cytoplasm and
becomes activated by certain low molecular weight chemicals.
Both murine and human AHR have been cloned and the basic
biochemistry has been worked out many years ago [1, 2].
Briefly, AHR sheds its chaperoning proteins (hsp90, c-src,
AIP, and others) upon ligand binding, which exposes a nuclear
translocation signal. AHR moves into the nucleus and dimer-
izes with AHR nuclear transporter (ARNT), another member
of the PAS-bHLH family. The complex induces transcription
of genes possessing conserved AHR binding sites (called
xenobiotic response elements, XREs) in their promoters.
Eventually, AHR is exported again into the cytosol and de-
graded [1, 3]. Many genes contain functional XREs, and AHR
regulates a plethora of genes in a cell-, tissue-, and condition-
specific fashion [4, 5]. The quality and duration of AHR
activation by various ligands directs level and spectrum of
the genes which are induced, and are thus pivotal in the
outcome, including a “toxic” outcome [6]. Three important
678
groups of genes are targeted by AHR. First, the battery of genes
responsible for metabolism of ring molecules, such as cyto-
chrome P (CYP) gene cyp1a1 or nqo1; second, genes related
to development, cell cycle, and cell differentiation; and finally,
genes related to immunity. Other highly cell-specific gene func-
tions can be found as well. It is increasingly appreciated that
AHR can cross-feed into other signaling pathways, such as
NFκB, allowing for a highly differentiated cellular response
[7]. Moreover, ligand activation dissociates the protein tyrosine
kinase pp60src from the cytosolic AHR complex, which can
move to the cell membrane-bound epidermal growth factor
receptor (EGFR), and thus trigger downstream MAPKs [8].
The AHR pathway is downregulated by the AHR repressor
(AHRR), a target gene of the AHR in a negative feedback loop.
The AHRR competes with AHR for the binding site of ARNT
and forms a transcriptionally inactive complex [9]. It may, more-
over, have functions beyond simple repression of AHR [10].
Expression levels of AHR are especially high in the liver
and in the barrier organs, such as lung, gut, and skin. This fits
well with both the traditionally well-known function of AHR
in xenobiotic metabolism and with its newly discovered roles
as a major player in the immune response and cell homeosta-
sis. Finally, AHR has a role in development of some organs
and tissues.
AHR is expressed in all skin cells, and endogenous ligands
are formed in situ from tryptophan via ultraviolet (UV) radia-
tion. Interestingly, chloracne and aberrant pigmentation are two
major adverse effects of exposure to the high-affinity AHR
ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a notori-
ously toxic environmental pollutant. Epidemiological identified
correlations between skin cancer and exposure to AHR ligands
in workers (such as coal miners) or by lifestyle (e.g., smokers)
are well known. Knowledge on the physiology of AHR in the
skin increased tremendously over the last years and highlighted
that AHR is involved in many aspects of skin physiology, such
as detoxification, cellular homeostasis, skin pigmentation, and
skin immunity. Here, we review the current knowledge of the
expression and function of AHR in the skin, and discuss the
therapeutic potential of manipulating this signaling system.
The skin—a layered organ with many functions
The skin is a layered organ of tightly connected cells. It has
three main layers, the subcutis, the dermis (mainly fibroblasts),
and the thinner outer epidermis (with keratinocytes (KC) as the
construction cells). Located in the dermis are sensory organs
for temperature and touch, hair bulbs, sebaceous glands, nerve
cells, blood vessels, and lymphatics, which serve as ports for
leukocyte migration in and out of the skin. The epidermis
serves critical functions in body protection. It is a physical/
mechanical, chemical, and biological barrier. It protects against
transcutaneous water loss, fights off microbes and viruses by
Semin Immunopathol (2013) 35:677–691
innate and adaptive immune responses, metabolizes and ex-
cludes external chemicals, and protects itself against DNA
damage by UV radiation via pigmentation and detection/
elimination of cancer cells. Furthermore, the skin has the
capacity to heal wounds. Keratinocyte stem cells are found at
the dermal/epidermal interface. They differentiate progressive-
ly and vertically from this basal stratum, first into strata of
metabolically active spinous and granular cells, which produce
keratin and lipids. Eventually, in the stratum corneum,
keratinocytes lose their nucleus and form a so-called cornified
envelope, a rigid structure composed of lipids enriched in
ceramides and cholesterol. The entire process renews the skin
continuously over lifetime. Interspersed and in direct contact
with the keratinocytes are melanocytes (MCs) (approximately
5 %), Langerhans cells (LCs) (1–3 %), the dendritic cells
(DCs) of the skin, αβ T cells, and T cells with an invariant
γδ T cell receptor (1–5 %). The latter are often referred to as
dendritic epidermal T cells due to their shape. Every LC and
MC is in contact with many keratinocytes, forming a tight
network. In addition, mast cells are located just underneath
the epidermis. The dermis—with fibroblasts as the structure
giving cell type—has an anatomically more complex structure
and higher cell diversity, it harbors macrophages, mast cells,
additional subsets of dendritic cells [11], and αβ T cells as
well, which vastly increase in numbers in the inflamed state.
For humans, it has been estimated that skin contains approxi-
mately 1 million T cells/cm2, thus there are more T cells in the
skin than in the blood [12]. The immunological challenge of
the skin is the balance between protecting against a constant
threat of pathogens while suppressing unnecessary and harm-
ful inflammation [13]. The skin is exposed to harmful or
damaging high energy UV radiation from the sun. Repair of
DNA damage, removal of dead cells if necessary, and surveil-
lance against cancer cells is therefore another vital task of the
skin. The AHR emerges as an important player in skin homeo-
stasis, as well as during infection and inflammation (Fig. 1).
Expression of the aryl hydrocarbon receptor in skin cells
It had been noted already in the 1990s that AHR expression
levels differed vastly between organs in both laboratory ani-
mals and in humans [2, 14, 15]. In these reports, liver and lung
were the organs with the highest AHR content, while muscle
and brain had very low levels. In the work from our institute,
we data-mined almost 2,000 published gene expression pro-
files from various tissues and cell lines, and identified lineage
and differentiation specific changes in AHR expression in T
cells and B cells [5]. More recently, various cell types, in
particular splenic B cells, T cells, and dendritic cells, were
sorted to high purity and analyzed for AHR mRNA or protein
expression [16]. With respect to the skin, most cell types of the
epidermis and fibroblasts in the dermis have been analyzed by
Semin Immunopathol (2013) 35:677–691
Fig. 1 Schematic overview of
skin structure and AHR
expression in skin cells. The
various cell populations and their
situation in skin are indicated. The
intensity of gray shading
indicates AHR expression levels.
White cells not studied, hatched
cells both AHR and AHR-
repressor expression were
reported
now. It is noteworthy that they all, without exception, have
high levels of AHR expression. The expression of AHR in
different cell types of the skin is summarized in Table 1.
Albeit, it appears self-evident that constitutive expression of
AHR is necessary for its action, no simple correlation exists
between expression levels, ligand sensitivity, strength of bio-
logical response, or biological importance of AHR for the cell
[5]. Most likely, expression level is one facet in the multilay-
ered regulation of this complex signaling pathway.
Natural and xenobiotic AHR ligands in the skin
are abundant
AHR can bind to and become activated by sterically planar
ligands with an approximate size of three benzene rings [17].
Ligands can be grouped in three ways. First, exogenous/
synthetic, such as the high-affinity pollutant TCDD and other
polycyclic aromatic hydrocarbons (PAH) (e.g., biphenyls, 7,12-
dimethylbenz[a]anthracene (DMBA), methylcholanthrene, or
benzo[a]pyrene (B[a]P)). A second group would be the
exogenous/natural compounds, which are found in or metabo-
lized from dietary plants such as glucosinolates, flavonoids, or
679
indolcarbinols. These substances can reach the skin either via
the food chain or by direct contact or topical application (e.g., if
they are present in cosmetics or sunscreens). Even the skin
microflora can produce ligands. Finally, endogenous AHR li-
gands are formed in the body, such as ITE, a tryptophan–cystein
dimer [17, 18], kynurenines, or 6-formylindolo[3,2-b]carbazole
(FICZ), a tryptophan dimer. Some place FICZ into the exoge-
nous group as it is generated under the exposure to UVB or solar
light, not via a metabolic pathway. Because different ligands
result in different outcomes [6, 17], it is generally assumed that
the nature of the ligand—availability, structure, half-life, etc.—
determines the AHR response [19]. There is still plenty of
unknown terrain, which needs to be covered in order to exploit
ligands therapeutically (Table 2).
FICZ generated by UV radiation
Directly in the skin, solar radiation and especially UVB gen-
erate tryptophan dimers of the indolo[3,2-b]carbazole type.
The UV/light-generated ligands were chemically characterized
and identified as FICZ and 6,12-diformylindolo[3,2-b]carba-
zole [20], and others. First detected in vitro (7), generation of
680 Semin Immunopathol (2013) 35:677–691

Table 1 Expression of AHR in skin cells

Mouse Human

Cell type (main functions) Constitutive AHR Reference Cell type AHR Reference
expression expression

Keratinocytes (barrier function, elasticity, filter out UV Yes [33] HaCaT (keratinocyte cell line) Yes [8]
damage, produce cytokines)
Langerhans cellsa (take up antigen, produce cytokines) Yes [33] Stem cell derived LC Yes [127]
Vγ5 γδ T cellsa (immunosurveillance, wound healing) Yes [102] γδ T cells ND
Melanocytes (pigmentation) Yes [53] Cultured foreskin melanocytes Yes [55]
Mast cells Yes [128] Yes [128]
Fibroblastsa (give pliability) Yes [129] Fibroblastsb Yes [10]
Sebocytes ND Cultured SZ95 sebocytes Yes [130]
linnegSca1neg bone marrow progenitors (as a source for Yes [131]
in vitro generated LC)

The table does not give quantitative measurements because expression levels cannot be compared across the various published data and between cell
types. In some papers, expression levels were compared to liver (which has one of the highest expressions in body tissues). It might be said, though, that
expression levels in all skin cell subsets is generally high. Expression was measured by either RT-PCR, Western blotting, or immunohistochemistry.
Where done, there appeared to be a good correlation between PCR-data and protein data. AHR is not or only very weakly expressed in naïve T cells,
muscle tissues, brain, and spleen (both in human and in mouse) [2, 132]; ND no data available
a
High AHR-repressor expression was reported in these cells
b
High AHR-repressor was reported in foreskin-derived fibroblasts, but not in adult fibroblast from mammary skin

such ligands by UVB irradiation was confirmed in vivo in AHR may serve as a sensor for UV radiation, and its formation
hepatocytes and keratinocytes as well [8, 21–23]. They have explains cutaneous as well as extracutaneous induction of
very high affinities to AHR, similar to TCDD, but are rapidly CYP1A1 enzyme activity after skin exposure to UV radiation
degraded within cells. Simple solar light suffices to generate [8, 27]. It remains to be shown, if UV also enhances metabo-
them, for example, in cell culture medium containing trypto- lism of polycyclic aromatic hydrocarbons and other environ-
phan, which was recognized as an experimental factor when mental pollutants to which humans are exposed; if so, this
comparing the suitability of commercial cell culture media could play a role in both activating and eliminating topical
with different tryptophan concentrations for Th17 differentia- carcinogenic substances. The balance might be critical [28]. In
tion, which is dependent on AHR [24]. One of these indoles, this context, it is interesting that KC and LC are differentially
1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole, was originally iso- efficient in xenobiotic metabolism, and the role of the UV-
lated in marine organisms [25, 26]. AHR signaling axis in relation to sensitivity against chemical-
FICZ is similar to TCDD in its lipophilicity, planarity, and induced cancer in this is unexplored [29]. Equally speculative,
shape. Its high-AHR affinity and easy degradability suggest it UV-generated FICZ might also provide an explanation for the
is an endogenous ligand. FICZ is degraded by CYP1A1, thus photosensitivity seen in lupus erythematosus. Conceivably,
regulates its own intracellular steady-state levels. Thus, the generation of FICZ could change the balance of regulatory T
cells toward inflammatory T cells (see below) [30]. Finally,
pigmentation protects the body against DNA damage by UV
Table 2 AHR ligands generated locally in/on skin radiation, and AHR as a sensor for UV light is involved in this
Ligand Source Evidence in skin vital function. In humans, sulfate conjugates of the compound
pathology or health FICZ were identified in 24-h urine [23], suggesting that they
(reference) may be active not only in the skin but in the body as well. It
will be interesting to see, if FICZ is an essential AHR ligand,
FICZ UV plus tryptophan (Sun) Graft rejection [133]
which—similar to Vitamin D—forms in the skin, but is need-
Kynurenine IDO metabolizes tryptophan Vitiligo [134]
(Langerhans cells)
ed “vitamin-like” not only in situ, but also in the whole body.
ICZ Yeast (Malassezia spec) Pityriasis versicolor,
Tryptanthrin, Yeast (Malassezia spec) cancer, [40, 135]
indirubin Kynurenines generated in inflammatory situations
Malassezin Yeast (Malassezia spec). Seborrheic dermatitis,
melanocyte apoptosis
[135, 136]
Catabolic breakdown of tryptophan generated via the so-
called kynurenine pathway leads to several neuroactive and
Semin Immunopathol (2013) 35:677–691
immunomodulatory metabolites. More to the point, several
kynurenines are potent AHR ligands, which have a role in the
adaptive differentiation of regulatory T cells [31]. While much
is yet unclear, it was recently shown that human dermal
fibroblasts and macrophages fully express the enzymes of
the kynurenine pathway [32]. The immunosuppressive en-
zyme indoleamine 2,3-dioxygenase (IDO) catalyzes the first
and rate-limiting step in tryptophan catabolism, generating
kynurenine. Recently, we showed that the ido gene is a target
of AHR in Langerhans cells [33], other authors found that
TCDD induces IDO in DCs derived from bone marrow cells
and that such DC promote Treg generation [31, 34]. Interest-
ingly, AHR-deficient dendritic cells do not upregulate IDO
after stimulation with LPS or IFNγ, and gene expression
profiling of Langerhans cells from AHR-deficient versus wild
type mice showed a virtual shutdown of ido transcription and
IDO enzyme activity by AHR deficiency [33, 34]. IDO can be
upregulated by proinflammatory cytokines, such as IFNγ or
TNFα, which in turn can be triggered in the skin upon UVB
exposure.
The physiological consequence of this is currently not
known, but it was suggested that IDO and tryptophan catab-
olites, especially kynurenine, might be involved in the forma-
tion of regulatory T cells and thus confer tolerance [31, 35,
36]. Interestingly, one study reported reduced tryptophan
levels in vitiligo skin, a common human depigmentation
disease [37]. AHR is vital to the regulation of melanogenesis
and melanocyte proliferation and differentiation through mod-
ulating the expressions of melanogenesis-related genes.
Thus, one can hypothesize scenarios, whereby sun radia-
tion via FICZ, AHR, and IDO sets off the kynurenine path-
way, eventually modulating the local and systemic AHR
response. Certainly, this line of research, i.e., the manipulation
of immune responses by AHR ligands, will attract more
attention in the future.
Indole compounds generated by skin-residing yeasts,
Malassezia spec
The stratum corneum can be colonized by various species of a
lipophilic yeast, Malassezia , e.g., Malassezia furfur and
Malassezia globosa. These Malassezia yeasts are present in
75∼80 % of healthy subjects, and besides of man, they are
also present on other warm-blooded animals. Many
Malassezia sp. convert tryptophan into indole compounds
[38], some of which are very potent AHR agonists. The
production of potent AHR ligands by Malassezia yeasts, such
as indirubin, indolo[3,2-b]carbazole, tryptanthrin and
malassezin, has been associated with the hyperproliferation
in seborrheic dermatitis and the absence of inflammation in
pityriasis versicolor [39]. Underlying mechanisms could be
AHR-mediated immune modulation and effects on cell cycle
(see below). Finally, as proposed by the group of Gaitanos, the
681
production of AHR ligands by Malassezia might contribute to
the risk of skin cancer, such as basal cell carcinomas via its
effects on cell cycle, DNA repair, reactive oxygen species
(ROS) production, induction of inflammatory cytokines, and
by its potential to suppress the immune system [40]. Further
work is needed to explore the role of Malassezia-derived
AHR ligands in skin pathology.
AHR involvement in toxic and physiological skin
responses
In the following, we will discuss the role of AHR for toxic
responses against environmental pollutants, as well as the
roles of AHR in healthy skin biology. Not surprisingly, the
roles of AHR are as diverse as the functions of the cells in
which AHR is expressed in the skin cells. Tables 3 and 4 give
an overview on this spectrum, and indicate where conse-
quences for human skin diseases were experimentally/
epidemiologically addressed or discussed on the background
of murine data. The therapeutic potential is obvious, although
no clinical trials are published as yet. However, various AHR
modulators are on trial for use against breast cancer [41, 42].
In our institute, studies are under way to treat vitiligo by AHR
manipulation.
Chloracne—the most striking human skin response
against TCDD and other PAHs
In humans, “chloracne” is the most striking toxic phenomenon
[43] after TCDD exposure, albeit its intensity does not strictly
correlate to exposure dose. Acneiform lesions and cysts were
first described in 1899 and named “chloracne” by Karl
Herxheimer, a famous Jewish dermatologist, who later died
in the concentration camp of Theresienstadt when he was
81 years old [44]. Chloracne lesions are caused by acute or
chronic exposure to dioxins, furans of biphenyls. Albeit great
improvements have been made to eliminate these substances
from the environment, cases of chloracne still occur to date
[45]. The mechanisms underlying chloracne are not well un-
derstood. Its pathology is characterized by hyperkeratinization
as well as a metaplastic response of the sebaceous glands.
Recently, the TCDD-induced skin lesions were recognized as
hamartomas which develop in parallel to a severe atrophy of
sebaceous glands. TCDD accumulates in these hamartomas,
and cyp1a1 is induced. Moreover, TCDD-dependent changes
in the transcriptome of the lesional tissue point to inhibition of
lipid metabolism [46].
Curiously, mice and other laboratory animals do not devel-
op chloracne-like diseases, albeit their keratinocytes are re-
sponsive to TCDD. The reasons for this—as for other species
differences regarding TCDD toxicity—are entirely unknown.
There are no data available on murine sebocytes and AHR. It
682 Semin Immunopathol (2013) 35:677–691

Table 3 Involvement of AHR and its ligands to skin cell and human disease

Skin cell type Evidence in human/mouse Outcome Human skin disease Ref.
discussed

Keratinocytes Human cell culture (SCC-12F, NHEK) Changed TGF-α, TGF-β2, and IL8 production Chloracne, Psoriasis, [137, 138]
after AHR ligand exposure palmoplantar pustulosis
Keratinocytes Human cell culture (NHEK, NIKS), Changed gene expression for keratinocyte Chloracne [93, 139, 140]
mouse (C57BL/J6) differentiation after TCDD exposure
Langerhans Mouse (C57BL/6) Impaired LC maturation and weak contact Contact hypersensitivity [33]
cells hypersensitivity in AHR−/− mice
Melanocytes Human cell culture (NHM, FM55, Upregulation of tyrosinase and MMP gene Skin cancer [55, 141]
A2058, HT-144, Bowes, expression after TCDD exposure
SK-MEL-2)
Melanocytes Mouse (C57BL/6, AhR−/−, AhRΔK5Cre) Impaired melanocyte increase in UVB Vitiligo [142]
exposed AHR−/− mice
Sebocytes Human cell culture (SZ95) Affected sebaceous gland differentiation Chloracne [53]
after TCDD exposure
T cells Mouse (C57BL/6, BALB/c) Affected skin graft survival after AHR ligand Skin graft rejection [133]
exposure
T cells Speculation Influence on inflammatory and autoimmune Psoriasis, atopic dermatis, [131]
diseases by AHR dependent IL-22 production sarcoidosis, SLE
Mast cells Primary mouse MC Enrichment in AhR/IL-6 and AhR/IL-17 (Chronic obstructive [128]
Human histology double-positive MCs within bronchial pulmonary disease)
lamina propria.

should be noted that this research also reveals a role for skin as
an important xenobiotic metabolizing organ, which produces
and induces cytochromes P450, epoxide hydroxylases, and
other enzymes. Both Langerhans cells and keratinocytes are
effective producers of such enzymes [33, 47], and their effi-
ciency for xenobiotic metabolism is related to its susceptibility
for chemically induced cancer as well as detailed in an elegant
study by Modi et al [29].
AHR: a new kid on the block mediating sun-induced
pigmentation
Tanning/pigmentation by proliferation of melanocytes and in-
creased melanin production is the vital response to protect skin
cells against UV radiation-induced DNA damage leading to
photocarcinogenesis, i.e., from basal cell carcinomas, squa-
mous carcinomas, and melanomas. Both increased proliferation
of melanocytes and enhanced melanogenesis underly the tan-
ning response. The sole producers of melanin are the melano-
cytes, which transfer melanin to keratinocytes via their den-
drites. Melanogenesis is a highly complex process, involving
approximately 150 genes. Keratinocytes provide α-MSH for
melanocytes, which activates the cAMP/PKA pathway, even-
tually resulting in tyrosinase transcription by melanocytes and
melanin production. Clinical observations after toxic exposures
suggested a link between AHR activation and melanogenesis.
In Japan in 1968 and in Taiwan in 1979, accidental mass
poisoning incidents occurred from cooking oil contaminated
with PCBs, amongst which are strong AHR ligands. Exposed
persons showed increased skin and gingival pigmentation, and

Table 4 Epidemiological or
clinical links between AHR li- Name of disease Evidence Reference
gands, AHR, and human skin
disease Vitiligo Association of AHR promoter [37, 56]
polymorphism with vitiligo in
a Han Chinese population
Differential expression of IDO
and c-kit in vitiligo lesions
Chloracne TCDD exposure Numerous, [45]
Psoriasis Histology, epidemiological association diMeglio et al., JID132, S15,079
(42nd Ann. Europ. Soc. of Dermatol.
Research Meeting), [143]
SLE UV light exacerbates disease [144]
Eosinophil Fasciitis Toxic oil diseases might trigger via [145]
tryptophan/UV/IDO
Enhanced skin Epidemiological correlation with air Vierkötter et al. submitted
aging pollution
Semin Immunopathol (2013) 35:677–691
children of mothers exposed to PCBs were born with dark
pigmentation of the head, face, and genitals (“cola-babies”)
[48–51]. Also, TCDD caused skin hyperpigmentation [52].
Biologically, UV radiation, more precisely UVB (290–
320 nm wavelength), is the most important modulator of skin
pigmentation. In line with the observations after chemical
(toxic) activation of AHR, our own work could show that
melanocytes functionally express AHR, and the mice needed
AHR to tan efficiently in standard UVB protocols. Both en-
hanced cell proliferation and tyrosine-induction were less effi-
cient in AHR knockout mice compared to wild-type mice.
Tanning responses and tyrosinase activity, however, were nor-
mal in keratinocyte-specific conditional AHR knockout mice,
indicating that the release of melanogenic keratinocyte factors
are unaffected by the UVB-AHR signaling pathway and that
the diminished tanning response in AHR knockout mice is
confined to the level of melanocytes. It is well known that the
c-kit/stem cell factor system is involved in melanocyte homeo-
stasis, and c-kit has functional XREs in its promoter which are
addressed by AHR [53, 54]. Melanogenesis was also inducible
in human cultured melanocytes by TCDD and FICZ [55].
Thus, the environmental sensor AHR links solar UVB radiation
to skin pigmentation. This finding is relevant for clinical appli-
cations, as it opens up the possibility of manipulating melano-
cyte proliferation (rather than mere chemical stimulation of
tyrosinase) as a therapeutic approach in diseases such as vitili-
go, a depigmentation disorder, or cosmetic problems such as
solar-induced lentigines in aging skin. Of note, a promoter
polymorphism of AHR in humans was linked to increased risk
for vitiligo as studied in a Han Chinese population [56], and
low c-kit levels are detected in vitiligo lesions and their periph-
eral areas [57].
The AHR is a central mediator of chemical skin
carcinogenesis
The oncogenic potential of the AHR was elegantly demonstrat-
ed using a transgenic mouse line that expresses a constitutively
active form of AHR. In contrast to their AHR-proficient litter-
mates, these transgenic mice developed severe tumors in the
glandular part of the stomach in absence of any additional
initiators or promoters [58]. Furthermore, a single injection
of N -nitrosodiethylamine was sufficient to induce
hepatocarcinogenesis in these transgenic animals [59], revealing
the tumor promoting properties of an overactivated AHR sys-
tem. These are probably due to AHR-dependent activation of
mitogenic and proinflammatory cytokines and growth factors,
such as COX-2, IL-8, IL-18, and amphiregulin [60, 61]. Mean-
while, numerous other publications also contributed to the
awareness that AHR triggers signaling processes relevant for
the development and progression of different types of cancer.
In the context of skin carcinogenesis, the AHR and down-
stream CYP enzymes were proven to be essential to unleash the
683
carcinogenic potential of PAH and related environmental pol-
lutants. PAHs can be found in cigarette smoke, combustion-
and traffic-derived particulate matter, and coal tar. Thus, our
skin, as a barrier organ, is frequently exposed to these carcino-
genic chemicals. Although nontoxic per se, PAHs are oxidized
by certain CYP enzymes, especially AHR-dependent
CYP1A1, CYP1A2, CYP1B1, and CYP2S1 [3], to enhance
their water solubility and enable conjugation to hydrophilic
moieties, such as activated sugar, sulfate, or glutathione. In case
the capacity of the conjugating enzyme system is exhausted,
PAH metabolites may attack the DNA to form highly muta-
genic adducts, which may be the initiating step for carcinogen-
esis. In addition, CYP-mediated reactions can cause a higher
production of ROS, resulting in oxidative damage of DNA [62]
and other macromolecules [63]. By now, it is broadly accepted
that cutaneous exposure to PAHs or PAH-containing formula-
tions can give rise to squamous cell carcinomas [64].
The probably best examined model of PAH relevant for
human exposure is B[a]P, which is sequentially metabolized
by CYP1A1 and microsomal epoxide hydrolase 1 (EPXH1) to
B[a]P-7,8-dihydrodiol-9,10-epoxide, an ultimate carcinogen
[65]. CYP1A1 expression is abolished in AHR-deficient
mice, and these animals are completely protected against
B[a]P carcinogenicity [66].
The metabolic activation of DMBA, another model PAH,
is mediated by CYP1A1, CYP1B1, and EPXH1 [67]. In a
classical two-stage carcinogenesis study using 12-O-
tetradecanoylphorbol-13-acetate as promoter, DMBA-exposed
mice developed cutaneous squamous cell carcinomas [29, 68].
The vast majority of these tumors harbored the activating codon
61 mutation in the Hras proto-oncogene [69]. Interestingly, the
carcinogenic potential of DMBA strongly depends on which
CYP1 isoform is predominantly expressed in the exposed cell
population or tissue [67]. In contrast to CYP1A1-mediated
DMBA metabolism (which favors detoxification), CYP1B1-
mediated metabolism of DMBA results in an enhanced forma-
tion of DMBA-trans-3,4-diol [70–72]. This metabolite is sub-
sequently transformed to the highly mutagenic DMBA-3,4-
diol-1,2-epoxide. In this context, a recent study revealed that
in keratinocytes, CYP1A1 is clearly higher expressed than
CYP1B1, whereas the latter is the dominating CYP enzyme
in Langerhans cells. Experimental depletion of epidermal
Langerhans cells protected mice against DMBA-induced skin
carcinogenesis, providing evidence that the generation of
DMBA-3,4-diol-1,2-epoxide is mediated exclusively by epi-
dermal Langerhans cells [29]. The basal and inducible expres-
sion of CYP1B1 is not only regulated by the AHR, but also by
other factors such as estrogen receptor-α [73] or effectors of
activated protein kinase A [74]. Accordingly, the rate of
CYP1B1 expression is still high enough in AHR KO mice to
toxify DMBA. Consequently, AHR KO mice were shown to
develop squamous cell carcinomas in comparable amounts to
AHR wild-type mice [67].
684
Although reports exist showing that CYP1-deficient mice
exhibit higher amounts of B[a]P-DNA adducts than the respec-
tive wild-type animals [75], a timely limited inhibition of the
AHR may probably result in a reduced metabolic activation of
environmental pollutants, and thus inhibit chemical carcino-
genesis. Regarding the usage of AHR antagonists as chemo-
preventive, compounds that attenuate ligand-activated AHR
signaling and simultaneously stimulate the Nrf2 system are
probably promising candidates to prevent severe health effects
provoked by environmental stressors [76]. As the master reg-
ulator of the antioxidant response, Nrf2 controls the expression
of numerous phase II conjugating enzymes, which are capable
of neutralizing ROS and reactive phase I metabolites [77].
Indeed, it was shown that co-exposure of mice to sulforaphane,
a dietary isothiocyanate, protected the mice against DMBA-
induced skin tumorigenesis via activation of Nrf2 signaling
[78], underscoring the importance of the capacity of the phase
II system in restraining chemical skin carcinogenesis.
Besides its involvement in chemical carcinogenesis, the fact
that the AHR is activated in response to UVB exposure implies
its possible contribution to photocarcinogenesis. The UVB-
stimulated activation of AHR in keratinocytes results in an
increased expression of CYP1A1, CYP1B1, and COX-2 [8,
27], whose enzyme-products may trigger photocarcinogenesis
[79]. Indeed, topical application of some plant polyphenols
that are known to antagonize AHR signaling, for instance
resveratrol or epigallocatechin-3-gallate [80, 81], were shown
to protect mice against UVB-induced skin carcinogenesis [82,
83]. Moreover, recent results from our laboratory disclose an
antiapoptotic function of the AHR in UVB-exposed human
and murine keratinocytes. Accordingly, a chemical inhibition
of AHR led to an enhanced removal of cells harboring irrep-
arable DNA damage (T.H.-S., unpublished observations).
Since apoptosis is regarded as one of the most important
mechanisms restraining carcinogenesis [84], these results
again point to a critical role of the AHR during skin cancer
development, which warrants further investigation.
AHR and the skin immune system
Immunity against pathogens on the skin while not attacking
the harmless commensals on the skin, immunosurveillance
against cancer cells and wound healing are important func-
tions of the skin. There are both resident antigen-presenting
cells and T cells in the skin, and during an immune response,
more cells immigrate, guided, e.g., by chemokine gradients.
AHR is relevant in all of these tasks.
AHR and the keratinocyte barrier function
Keratinocytes are the first line of defense in the skin immune
system. They secrete many cytokines and possess toll-like
Semin Immunopathol (2013) 35:677–691
receptors (TLRs). They are pivotal in mobilizing leukocytes
from blood and orchestrate the participation of dermal cells in
an immune response. AHR was identified as a crucial medi-
ator of the UVB stress response in human keratinocytes,
which triggers activation of the EGFR and downstream
MAPK cascades upon UVB exposure. Activation of MAPK
is relevant for UVB-induced skin inflammation and
photocarcinogenesis [85]. Again, FICZ is the relevant ligand.
It was an exciting finding that AHR might not only trigger the
classical nuclear events of DNA transcription. Thus, dissolu-
tion of the cytosolic AHR complex releases c-src, which in
turn binds to EGFR and initiates MAPK signaling, resulting in
the upregulation of target genes, e.g., COX-2 [8]. Interesting-
ly, EGFR activation inhibits many processes in keratinocyte
differentiation, and was shown in organotypic cultures of
human skin to impair epidermal integrity. Many EGFR-
targeted genes are related to skin diseases [86]. Sutter and
coworkers recently reported that EGF represses the dioxin-
mediated induction of CYP1A1 in cultured normal human
keratinocytes by inhibiting the recruitment of the transcrip-
tional coactivator protein p300 to the CYP1A1 gene. TCDD
accelerates keratinocyte differentiation and the formation of
the cornified envelope [87], and blocking or manipulating
EGFR signaling was suggested as a therapeutic option in
dioxin-like skin pathologies.
Although a direct study on AHR-mediated EGFR trigger-
ing in skin diseases has not been done so far, the data
and observations fit well with the results from a mouse
model which express a constitutively activate AHR in its
keratinocytes. This mouse line develops severe skin lesions
with itching, skin inflammation, and immunological imbal-
ance. Together, this resembled typical atopic dermatitis, a
chronic inflammatory disorder characterized by a defect in
epidermal barrier function [61]. Also, keratinocyte-specific
ARNT-deficient mice die shortly after birth due to severe
dehydration, caused by a defect in normal lipid production
by keratinocytes [88].
What about AHR and cytokines in keratinocytes?
Keratinocytes express an impressive arsenal of cytokines
[89]. They produce proinflammatory ones such as IL1β
or TNFα, as well as those controlling growth (IL-6, stem
cell factor), and immunosuppressive cytokines (TGF-β),
chemokines (IL-8), and more [90], many of which have XREs
in their promoters [4, 91]. Direct evidence shows that IL1β
[92] and IL-8 are targets of AHR. IL-8 is induced in human
keratinocytes by B[a]P—a chemical found also in cigarette
smoke—and IL-8 is related to inflammatory skin diseases
[93]. In wound healing, levels of TGF-β are decisive for
epithelization and migration of keratinocytes to close wounds.
Delayed wound healing causes chronic skin lesions such as
those found in diabetes. Fernandez-Salguero and his group
showed in AHR-deficient mice that an increased TGF-β
production by fibroblasts led to faster re-epithelization and a
Semin Immunopathol (2013) 35:677–691
higher collagen content. Possibly, down-modulation of AHR
could be used to improve wound healing [94].
AHR and dendritic cells of the skin
LC make up 1–3 % of the epidermal cells. As DC, they
acquire, process, and subsequently present both foreign and
self-antigens to T lymphocytes in lymphoid organs. Several
years ago, in a shift of paradigm, evidence emerged that LC—
beyond initiating contact hypersensitivity [95]—have regula-
tory and tolerogenic functions [96]. Furthermore, LC was
shown to be unable to elicit T cell responses to certain viral
antigens [97, 98]. In 1989, Puhvel et al. [99] investigated
density and morphology of LC in HRS/J mice, a murine
model for skin effects of TCDD. They reported that LC from
TCDD-treated hairless mice were smaller and had fewer den-
dritic protrusions than controls. We showed that LC
Langerhans cells express AHR (and also AHRR) at high
levels [33]. AHR-deficient LC was impaired in maturation;
they remained smaller and less granular, and did not
upregulate expression of co-stimulatory molecules CD40,
CD80, and CD24 during in vitro maturation. Likewise, their
phagocytic capacity did not decrease (another sign of imma-
turity). GMCSF, needed for LC maturation, was secreted in
significantly lower amounts by AHR-deficient epidermal
cells, largely due to invariant γδ T cells [100]. The data
suggests that the AHR is involved in LC maturation, both
cell-autonomously and through by-stander cells. TCDD injec-
tion of mice did not lead to upregulation of CYP1A1 in LC;
this might be related to the high constitutive levels of AHRR
and might be part of a risk strategy against protein-reactive
generation of chemical skin allergens [101, 102].
Contact hypersensitivity is impaired in AHR deficient
mice, which is in agreement with the impaired maturation of
AHR-deficient LC. We have observed that AHR−/−LC retain
their capacity to migrate into LN after hapten challenge (C.E.,
unpublished observation). Contact hypersensitivity is compa-
rable between WT mice and mice with conditional ablation of
AHR in KC only, suggesting that the impairment is caused by
an intrinsic LC effect (C.E., unpublished data). Blocking of
the AHR signal in LC may help to relieve allergic skin symp-
toms because many xenobiotics, including those metabolized
via the AHR pathway, can exacerbate allergic reactions [102].
Transgenic mice with a constitutively active AHR in KC
develop skin lesions accompanied by inflammation and im-
munological imbalances resembling typical atopic dermatitis
[61], and TCDD exacerbates atopic dermatitis [103]. The
underlying mechanism is not clear, albeit the triggering events
might be a break of the skin barrier, followed by inflammation.
A second highly interesting angle is the role of AHR for
IDO expression, both by LC and bone marrow-derived DC.
Both constitutive and inducible expression of IDO requires
presence of AHR in the cells. IDO regulates immune responses
685
through its capacity to degrade the essential amino acid tryp-
tophan into kynurenine and other downstream metabolites,
which suppress effector T cell function and favor the differen-
tiation of regulatory T cells. DC and certain tumors can express
the ido gene. IDO-mediated tolerogenicity and acquired im-
mune privilege has been identified as a potential target for
therapeutical strategies in inflammatory and autoimmune dis-
eases, such as collagen arthritis or diabetes [53, 56]. Unexpect-
edly, IDO enzyme activity was not inducible by LPS or IFN-γ
in bone marrow-derived DC from AHR-deficient mice [33,
34]. As AHR is known to interact with NFκB [104], it is likely
that ido induction by AHR does not use the “classical” AHR/
ARNT pathway described above, but ties into NFκB signaling
[7, 105]. Data for dermal DC are not available. What could be
the consequence of IDO as a target of AHR in LC/DC?
Kynurenines produced by DC can induce Treg directly [31],
and this might explain how DC can promote Treg formation in
an AHR-dependent manner. Currently, this was shown only
in vitro, but conceivably, it could be a previously unrecognized
mechanism on how the skin calms overshooting inflammatory
reactions. At the same time, the ligand FICZ promotes gener-
ation of Th17 from naive T cells [24, 106, 107]. Interestingly,
in human atopic skin or psoriatic lesional skin, the levels of ido
are higher than in uninvolved skin [108]. It is currently difficult
to solve these seemingly contradictory findings, and more
research is needed before designing therapeutic strategies for
skin diseases [109].
AHR and IL17, IL22, and IL23
As was first shown by two seminal papers in 2008 [106, 107]
and soon studied in increasing details, AHR is a necessary
factor for the production of IL-22 by Th17 T cells, and for the
differentiation balance of Th17 and/or inducible Foxp3+ Treg
and the generation of Tr1 cells [24, 105, 107, 110, 111]. Th17
cells are a new effector subset of T cells, and pivotal for
fighting bacteria. They also contribute to the exacerbation of
autoimmune diseases; thus, it is essential that they are tightly
controlled. AHR activity promotes their expansion and is
obligatory for IL-22 production. By now, the picture is at the
same time more detailed and infinitely more complex; in
particular, it emerged that AHR also promotes IL21 and
IL23 production and has, dependent on the ligand, also inhib-
itory effects on Th17 [31]. The skin has several subsets of IL-
17 producing cells (see also below), which may not be sur-
prising considering for a site of constant bacterial exposure.
Also in γδ T cells, IL-22 is controlled by AHR activity [13]. In
humans, LC induces a special subset of T cells, Th22, which
produce IL-22 but not IL-17 [112]. Again, IL-22 is under the
control of AHR [113]. IL-22 participates in many chronic
inflammatory conditions, including in the skin. It promotes
KC hyperplasia and epidermal remodeling in 3D cultures, and
has been suggested as a target in the treatment of psoriasis
686
[114]. Many questions remain, both regarding the AHR-
dependent regulation of these cytokines in skin homeostasis
and during skin pathologic disease conditions, as well as the
associated therapeutic options. Regarding the role of AHR in
changing the balance of regulatory T cells versus Th17 cells,
AHR has been suggested as a target to combat autoimmune
disorders [111, 115]. Eventually, it will be important to study
whether and how skin-resident T cells are sensitive to ligand-
mediated AHR activation in situ, and whether their plasticity
is affected by AHR, or whether the fate of T cells which
immigrate into skin upon inflammation can be manipulated
by AHR.
AHR and skin gamma–delta cells
The murine epidermis harbors a special subset of TCRγδ + T
cells with a restricted repertoire of Vγ3/Jγl-Cγ1 and Vδ1/Jδ2/
Jδ2-Cδ (according to the nomenclature by Garmann, Cell
1986). These skin TCRγδ + T cells are also called dendritic
epidermal T cells (DETC) because of their morphology. Mice
deficient in the tcrd gene, and thus without any TCRγδ +
(neither in the periphery nor in the skin), have increased
sensitivity to carcinogen-induced skin carcinogenesis and
wound repair [116]. Interestingly, most γδ T cells are an
important source of IL17 and IL22, and—similar to Th17
cells—AHR is required for IL22 production [117]. As they
express TLRs, they are uniquely suited for quickly fighting
bacterial infections, before the adaptive immune response
kicks in. High AHR expression has been shown in murine
DETC, gut intraepithelial lymphocytes, and in a subset of
peripheral IL-17 producing TCRγδ + T cells [100, 117,
118]. We found that DETC can seed the skin after birth, but
do not proliferate in situ and are quickly lost in AHR-deficient
mice. In contrast to tcrd −/− mice (which are γδ T cell deficient
in the periphery as well), DETC are not replaced by αβ T
cells, making AHR-deficient mice a unique model to study
DETC function [100]. The molecular mechanism for this loss
is not altogether clear, but evidence points to the reduced
expression of c-kit, which is a direct target of AHR, and
needed for γδ T cell homeostasis. DETC are a major source
of GMCSF and other cytokines in the skin, their lack affects
LC and KC as well [116].
Human skin has more TCRαβ + T cells and fewer γδ T
cells than murine skin. Also in human skin, γδ T cells secrete
cytokines, are important immunosurveillance [119, 120], and
presumably participate in the control of epithelial integrity
[121]. The human-resident T cells are mainly memory-type
CD8+ αβTCR + T cells in the epidermis and cutaneous
lymphocyte antigen expressing CD4+ and CD8+ T cells in
the dermis [12, 13]. Conventional T cells of the Th1, Th2, and
Th17 type migrate into the skin during various inflammatory
diseases. Recently, it was found that invariant Vγ9 T cells
migrate from blood into psoriatic lesions [122], and γδ T cells
Semin Immunopathol (2013) 35:677–691
are a major source of IL17 in skin [123]. Also, Th17 cells are
found in psoriasis and atopic dermatitis, and are pivotal for
defense against bacterial and fungal infections [13].
Considering the role of γδ T cells in skin immuno-
surveillance, and their responsiveness to AHR signaling, it
will be exciting to follow further how environmental cues
such as UV light (generating FICZ) or TLR activation by
commensal or pathogenic bacteria (possibly connecting
AHR to NFκB signaling) triggers and shapes skin immunity.
Conclusions and outlook
Research on AHR as a sensor linking the environment to
physiological functions has moved with impressive speed
over the last years, far beyond the decade-long studies in
toxicology of the AHR. In particular, immunological and
oncological questions are studied. It was soon recognized that
there is a strong ligand-dependent and cell-type dependent
complexity in outcome of AHR activation, in addition to
dose-effects, the bifurcated quality of signaling via c-src in
the cytoplasm and AHR/ARNT, and finally its potential to tie
into other signaling pathways such as NFκB. This paper, and
the other ones in this special issue of Seminars in Immunopa-
thology, gives an idea of the impressive range of AHR effects
and its underlying cellular events. Unfortunately, AHR has not
been crystallized until now, hampering structure-activity stud-
ies of AHR and its ligands. This certainly is a huge gap in
AHR research.
Nonetheless, AHR is uniquely suited for therapeutic ap-
proaches or chemopreventive strategies. This type of research
is most advanced regarding cancer such as breast cancer and
brain tumors. The group of Stephen Safe has tested pharma-
ceuticals already in clinical use, which have AHR agonist
capacity (e.g., leflunomide, tranilast, 4-hydroxytamoxifen,
omeprazole, and others). They and others reported the effects
on breast cancer cells suggesting their clinical potential for
treatment of breast cancer via AHR-ER inhibitory cross-talk
[41, 124] and have labeled such molecules selective AHR
modulators. Interestingly, tranilast is also used in treatment
of atopic dermatitis. Tryptophan degradation/kynurenine gen-
eration by brain tumor cells appears to be a strategy to escape
the immune system in an AHR-dependent manner, and this
novel mechanism might have broader implications in the
relationship of inflammation and cancer in general [125]. In
particular, FICZ was considered a novel target [126], and plant
polyphenols (e.g., green tee polyphenols, flavonoids, and
many more) have been studied for their use in skin cancer,
as recently reviewed by Korkina and coworkers [127]. Re-
garding therapy, suitable AHR ligands can be integrated into
creams without the solvent or logistic problems associated
with large protein biologics.
Semin Immunopathol (2013) 35:677–691
In conclusion, AHR is an important player in skin physi-
ology, and although much is still unclear, AHR emerges as a
target for prevention and therapy of skin diseases. It will be
exciting to see more and more data, both from basic research
as from clinical studies in the near future.
Acknowledgments Research of C.E. is supported by grants from the
Deutsche Forschungsgemeinschaft (DFG ES103/5-1 and 103/6-1). H.W.
is supported by DFG WE2625/2-1 and the Leibnizgemeinschaft
(SenatsausschussWettbewerb 2012). J.K. is supported by DFG FG871
and the ‘Bundesministerium für Bildung und Forschung Verbundprojekt
UV’.
References
1. Schmidt JV, Bradfield CA (1996) Ah receptor signaling pathways.
Annu Rev Cell Dev Biol 12:55–89
2. Dolwick KM, Schmidt JV, Carver LA, Swanson HI, Bradfield CA
(1993) Cloning and expression of a human Ah receptor cDNA. Mol
Pharmacol 44(5):911–917
3. Abel J, Haarmann-Stemmann T (2010) An introduction to the
molecular basics of aryl hydrocarbon receptor biology. Biol Chem
391(11):1235–1248
4. Sun YV, Boverhof DR, Burgoon LD, Fielden MR, Zacharewski TR
(2004) Comparative analysis of dioxin response elements in human,
mouse and rat genomic sequences. Nucleic Acids Res 32(15):4512–
4523
5. Frericks M, Meissner M, Esser C (2007) Microarray analysis of the
AHR system: tissue-specific flexibility in signal and target genes.
Toxicol Appl Pharmacol 220(3):320–332
6. Mitchell KA, Elferink CJ (2009) Timing is everything: conse-
quences of transient and sustained AhR activity. Biochem
Pharmacol 77(6):947–956
7. Wu D, Li W, Lok P, Matsumura F, dam Vogel CF (2011) AhR
deficiency impairs expression of LPS-induced inflammatory genes
in mice. Biochem Biophys Res Commun 410(2):358–363
8. Fritsche E, Schafer C, Calles C, Bernsmann T, Bernshausen T,
Wurm M et al (2007) Lightening up the UV response by identifi-
cation of the arylhydrocarbon receptor as a cytoplasmatic target for
ultraviolet B radiation. Proc Natl Acad Sci USA 104(21):8851–
8856
9. Mimura J, Ema M, Sogawa K, Fujii-Kuriyama Y (1999) Identifi-
cation of a novel mechanism of regulation of Ah (dioxin) receptor
function. Genes Dev 13(1):20–25
10. Tigges J, Weighardt H, Wolff S, Gotz C, Forster I, Kohne Z, et al.
(2012) Aryl Hydrocarbon Receptor Repressor (AhRR) function
revisited: repression of CYP1 activity in human skin fibroblasts is
not related to AhRR expression. J Invest Dermatol
11. Romani N, Clausen BE, Stoitzner P (2010) Langerhans cells and
more: langerin-expressing dendritic cell subsets in the skin.
Immunol Rev 234(1):120–141
12. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K,
Dowgiert RK et al (2006) The vast majority of CLA + T cells are
resident in normal skin. J Immunol 176(7):4431–4439
13. Nestle FO, Di MP, Qin JZ, Nickoloff BJ (2009) Skin immune
sentinels in health and disease. Nat Rev Immunol 9(10):679–691
14. Carlstedt-Duke JM (1979) Tissue distribution of the receptor for
2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Cancer Res
39(8):3172–3176
15. Li W, Donat S, Dohr O, Unfried K, Abel J (1994) Ah receptor in
different tissues of C57BL/6 J and DBA/2 J mice: use of
687
competitive polymerase chain reaction to measure Ah-receptor
mRNA expression. Arch Biochem Biophys 315(2):279–284
16. Esser C (2012) The physiological role of AHR in the mouse
immune system. In: Pojhanvirta R (ed) The AH receptor in biology
and toxicology. Ref Type: Serial (Book,Monograph). Wiley&Sons,
Hoboken, pp 499–510
17. Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon
receptor by structurally diverse exogenous and endogenous
chemicals. Annu Rev Pharmacol Toxicol 43:309–334
18. Nguyen LP, Bradfield CA (2008) The search for endogenous acti-
vators of the aryl hydrocarbon receptor. Chem Res Toxicol
21(1):102–116
19. Denison MS, Soshilov AA, He G, DeGroot DE, Zhao B (2011)
Exactly the same but different: promiscuity and diversity in the
molecular mechanisms of action of the aryl hydrocarbon (dioxin)
receptor. Toxicol Sci 124(1):1–22
20. Rannug U, Rannug A, Sjoberg U, Li H, Westerholm R, Bergman J
(1995) Structure elucidation of two tryptophan-derived, high affin-
ity Ah receptor ligands. Chem Biol 2(12):841–845
21. Rannug A, Rannug U, Rosenkranz HS, Winqvist L, Westerholm R,
Agurell E et al (1987) Certain photooxidized derivatives of trypto-
phan bind with very high affinity to the Ah receptor and are likely to
be endogenous signal substances. J Biol Chem 262(32):15422–
15427
22. Diani-Moore S, Labitzke E, Brown R, Garvin A, Wong L, Rifkind
AB (2006) Sunlight generates multiple tryptophan photoproducts
eliciting high-efficacy CYP1A induction in chick hepatocytes and
in vivo. Toxicol Sci 90(1):96–110
23. Wincent E, Amini N, Luecke S, Glatt H, Bergman J, Crescenzi C
et al (2009) The suggested physiologic aryl hydrocarbon receptor
activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]
carbazole is present in humans. J Biol Chem 284(5):2690–2696
24. Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B
(2009) Natural agonists for aryl hydrocarbon receptor in culture
medium are essential for optimal differentiation of Th17 T cells. J
Exp Med 206(1):43–49
25. Diani-Moore S, Ma Y, Labitzke E, Tao H, David WJ, Anderson J
et al (2011) Discovery and biological characterization of 1-(1H-
indol-3-yl)-9H-pyrido[3,4-b]indole as an aryl hydrocarbon receptor
activator generated by photoactivation of tryptophan by sunlight.
Chem Biol Interact 193(2):119–128
26. Hahn ME (2002) Aryl hydrocarbon receptors: diversity and evolu-
tion. Chem Biol Interact 141(1–2):131–160
27. Katiyar SK, Matsui MS, Mukhtar H (2000) Ultraviolet-B exposure
of human skin induces cytochromes P450 1A1 and 1B1. J Invest
Dermatol 114(2):328–333
28. Ma Q, Lu AY (2007) CYP1A induction and human risk assessment:
an evolving tale of in vitro and in vivo studies. Drug Metab Dispos
35(7):1009–1016
29. Modi BG, Neustadter J, Binda E, Lewis J, Filler RB, Roberts SJ et al
(2012) Langerhans cells facilitate epithelial DNA damage and squa-
mous cell carcinoma. Science 335(6064):104–108
30. Martin R, O’Shea J, Birnbaum LS, Luebke R (2008) Community
corner. Striking the balance in multiple sclerosis. Nat Med
14(5):491
31. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ,
Bradfield CA (2010) An interaction between kynurenine and the
aryl hydrocarbon receptor can generate regulatory T cells. J
Immunol 185(6):3190–3198
32. Asp L, Johansson AS, Mann A, Owe-Larsson B, Urbanska EM,
Kocki T et al (2011) Effects of proinflammatory cytokines on
expression of kynurenine pathway enzymes in human dermal fibro-
blasts. J Inflamm (Lond) 8:25
33. Jux B, Kadow S, Esser C (2009) Langerhans cell maturation and
contact hypersensitivity are impaired in aryl hydrocarbon receptor-
null mice. J Immunol 182(11):6709–6717
688
34. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara
K et al (2010) Aryl hydrocarbon receptor negatively regulates
dendritic cell immunogenicity via a kynurenine-dependent mecha-
nism. Proc Natl Acad Sci U S A 107(46):19961–19966
35. Mellor AL, Munn DH (2004) IDO expression by dendritic cells:
tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762–
774
36. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara
GB (2002) Tryptophan-derived catabolites are responsible for inhi-
bition of T and natural killer cell proliferation induced by
indoleamine 2,3-dioxygenase. J Exp Med 196(4):459–468
37. Schallreuter KU, Salem MA, Gibbons NC, Maitland DJ, Marsch E,
Elwary SM et al (2012) Blunted epidermal L -tryptophan metabo-
lism in vitiligo affects immune response and ROS scavenging by
Fenton chemistry, part 2: epidermal H2O2/ONOO(−)-mediated
stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl
hydrocarbon receptor-mediated immune response signaling.
FASEB J 26(6):2471–2485
38. Wille G, Mayser P, Thoma W, Monsees T, Baumgart A, Schmitz HJ
et al (2001) Malassezin–A novel agonist of the arylhydrocarbon
receptor from the yeast Malassezia furfur. Bioorg Med Chem
9(4):955–960
39. Vlachos C, Schulte BM, Magiatis P, Adema GJ, Gaitanis G (2012)
Malassezia-derived indoles activate the aryl hydrocarbon receptor
and inhibit toll-like receptor-induced maturation in monocyte-
derived dendritic cells. Br J Dermatol 167(3):496–505
40. Gaitanis G, Velegraki A, Magiatis P, Pappas P, Bassukas ID (2011)
Could Malassezia yeasts be implicated in skin carcinogenesis
through the production of aryl-hydrocarbon receptor ligands? Med
Hypotheses 77(1):47–51
41. Jin UH, Lee SO, Safe S (2012) Aryl hydrocarbon receptor (AHR)-
active pharmaceuticals are selective AHR modulators in MDA-MB-
468 and BT474 breast cancer cells. J Pharmacol Exp Ther
343(2):333–341
42. Tiong CT, Chen C, Zhang SJ, Li J, Soshilov A, Denison MS et al
(2012) A novel prenylflavone restricts breast cancer cell growth
through AhR-mediated destabilization of ERalpha protein. Carci-
nogenesis 33(5):1089–1097
43. Caputo R, Monti M, Ermacora E, Carminati G, Gelmetti C, Gianotti
R et al (1988) Cutaneous manifestations of tetrachlorodibenzo-p-
dioxin in children and adolescents. Follow-up 10 years after the
Seveso, Italy, accident. J Am Acad Dermatol 19(5 Pt 1):812–819
44. Scholz A (2012) Karl Herxheimer - Geheimrat mit dem gelben
Stern. J Dtsch Dermatol Ges 10(12):925–927
45. Passarini B, Infusino SD, Kasapi E (2010) Chloracne: still cause for
concern. Dermatology 221(1):63–70
46. Saurat JH, Kaya G, Saxer-Sekulic N, Pardo B, Becker M,
Fontao L et al (2012) The cutaneous lesions of dioxin exposure:
lessons from the poisoning of Victor Yushchenko. Toxicol Sci
125(1):310–317
47. Gotz C, Pfeiffer R, Tigges J, Blatz V, Jackh C, Freytag EM et al
(2012) Xenobiotic metabolism capacities of human skin in compar-
ison with a 3D epidermis model and keratinocyte-based cell culture
as in vitro alternatives for chemical testing: activating enzymes
(Phase I). Exp Dermatol 21(5):358–363
48. Kikuchi M (1984) Autopsy of patients with yusho. Prog Clin Biol
Res 137:19–30
49. Kanagawa Y, Matsumoto S, Koike S, Tajima B, Fukiwake N,
Shibata S et al (2008) Association of clinical findings in
Yusho patients with serum concentrations of polychlorinated
biphenyls, polychlorinated quarterphenyls, and 2,3,4,7,8-
pentachlorodibenzofuran more than 30 years after the poisoning
event. Environ Health 7:47
50. Masuda Y (1985) Health status of Japanese and Taiwanese after
exposure to contaminated rice oil. Environ Health Perspect 60:321–
325
Semin Immunopathol (2013) 35:677–691
51. Hashiguchi I, Yoshimine Y, Maeda H, Gotou Y, Ishikawa M, Fujii S
et al (2007) Epidemiologic examination on the prevalence of the
periodontal diseases and oral pigmentation in Yusho patients in
2006. Fukuoka Igaku Zasshi 98(5):170–175
52. Dunagin WG (1984) Cutaneous signs of systemic toxicity due to
dioxins and related chemicals. J Am Acad Dermatol 10(4):688–700
53. Jux B, Kadow S, Luecke S, Rannug A, Krutmann J, Esser C (2011)
The aryl hydrocarbon receptor mediates UVB radiation-induced
skin tanning. J Invest Dermatol 131(1):203–210
54. Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C
et al (2011) Natural aryl hydrocarbon receptor ligands control
organogenesis of intestinal lymphoid follicles. Science. doi:10.
1126/science.1214914
55. Luecke S, Backlund M, Jux B, Esser C, Krutmann J, Rannug A
(2010) The aryl hydrocarbon receptor (AHR), a novel regulator of
human melanogenesis. Pigment Cell Melanoma Res 23(6):828–833
56. Wang XW, Li K, Guo S, Qiang HN, Liu L, Song P et al (2012) The
association of functional polymorphisms in the aryl hydrocarbon
receptor (AHR) gene with the risk of vitiligo in Han Chinese
populations. Br J Dermatol 166(5):1081–1087
57. Kitamura R, Tsukamoto K, Harada K, Shimizu A, Shimada S,
Kobayashi T et al (2004) Mechanisms underlying the dysfunction
of melanocytes in vitiligo epidermis: role of SCF/KIT protein
interactions and the downstream effector, MITF-M. J Pathol
202(4):463–475
58. Andersson P, McGuire J, Rubio C, Gradin K, Whitelaw ML,
Pettersson S et al (2002) A constitutively active dioxin/aryl hydro-
carbon receptor induces stomach tumors. Proc Natl Acad Sci U S A
99(15):9990–9995
59. Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C,
Poellinger L et al (2004) A constitutively active dioxin/aryl hydro-
carbon receptor promotes hepatocarcinogenesis in mice. Cancer Res
64(14):4707–4710
60. Haarmann-Stemmann T, Bothe H, Abel J (2009) Growth factors,
cytokines, and their receptors as downstream targets of aryl hydro-
carbon receptor (AhR) signaling pathways. Biochem Pharmacol
77(4):508–520
61. Tauchi M, Hida A, Negishi T, Katsuoka F, Noda S, Mimura J et al
(2005) Constitutive expression of aryl hydrocarbon receptor in
keratinocytes causes inflammatory skin lesions. Mol Cell Biol
25(21):9360–9368
62. Xue W, Warshawsky D (2005) Metabolic activation of polycyclic
and heterocyclic aromatic hydrocarbons and DNA damage: a re-
view. Toxicol Appl Pharmacol 206(1):73–93
63. Godschalk R, Curfs D, Bartsch H, van Schooten FJ, Nair J (2003)
Benzo[a]pyrene enhances lipid peroxidation induced DNA damage
in aorta of apolipoprotein E knockout mice. Free Radic Res
37(12):1299–1305
64. Diepgen TL, Mahler V (2002) The epidemiology of skin cancer. Br
J Dermatol 146(Suppl 61):1–6
65. Gelboin HV (1980) Benzo[alpha]pyrene metabolism, activation,
and carcinogenesis: role and regulation of mixed-function oxidases
and related enzymes. Physiol Rev 60(4):1107–1166
66. Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H,
Mimura J et al (2000) Benzo[a]pyrene carcinogenicity is lost in
mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci U S
A 97(2):779–782
67. Ide F, Suka N, Kitada M, Sakashita H, Kusama K, Ishikawa T
(2004) Skin and salivary gland carcinogenicity of 7,12-
dimethylbenz[a]anthracene is equivalent in the presence or absence
of aryl hydrocarbon receptor. Cancer Lett 214(1):35–41
68. Hennings H, Devor D, Wenk ML, Slaga TJ, Former B, Colburn NH
et al (1981) Comparison of two-stage epidermal carcinogenesis
initiated by 7,12-dimethylbenz(a)anthracene or N-methyl-N’-nitro-
N-nitrosoguanidine in newborn and adult SENCAR and BALB/c
mice. Cancer Res 41(3):773–779
Semin Immunopathol (2013) 35:677–691
69. Balmain A, Ramsden M, Bowden GT, Smith J (1984) Activation of
the mouse cellular Harvey-ras gene in chemically induced benign
skin papillomas. Nature 307(5952):658–660
70. Buters J, Quintanilla-Martinez L, Schober W, Soballa VJ,
Hintermair J, Wolff T et al (2003) CYP1B1 determines susceptibil-
ity to low doses of 7,12-dimethylbenz[a]anthracene-induced ovar-
ian cancers in mice: correlation of CYP1B1-mediated DNA adducts
with carcinogenicity. Carcinogenesis 24(2):327–334
71. Savas U, Carstens CP, Jefcoate CR (1997) Biological oxidations
and P450 reactions. Recombinant mouse CYP1B1 expressed in
Escherichia coli exhibits selective binding by polycyclic hydrocar-
bons and metabolism which parallels C3H10T1/2 cell microsomes,
but differs from human recombinant CYP1B1. Arch Biochem
Biophys 347(2):181–192
72. Wislocki PG, Gadek KM, Chou MW, Yang SK, Lu AY (1980)
Carcinogenicity and mutagenicity of the 3,4-dihydrodiols and other
metabolites of 7,12-dimethylbenz(a)anthracene and its
hydroxymethyl derivatives. Cancer Res 40(10):3661–3664
73. Tsuchiya Y, Nakajima M, Kyo S, Kanaya T, Inoue M, Yokoi T
(2004) Human CYP1B1 is regulated by estradiol via estrogen
receptor. Cancer Res 64(9):3119–3125
74. Zheng W, Jefcoate CR (2005) Steroidogenic factor-1 interacts with
cAMP response element-binding protein to mediate cAMP stimu-
lation of CYP1B1 via a far upstream enhancer. Mol Pharmacol
67(2):499–512
75. Uno S, Dalton TP, Shertzer HG, Genter MB, Warshawsky D,
Talaska G et al (2001) Benzo[a]pyrene-induced toxicity: paradoxi-
cal protection in Cyp1a1(−/−) knockout mice having increased
hepatic BaP-DNA adduct levels. Biochem Biophys Res Commun
289(5):1049–1056
76. Haarmann-Stemmann T, Abel J, Fritsche E, Krutmann J (2012) The
AhR-Nrf2 pathway in keratinocytes: on the road to chemopreven-
tion? J Invest Dermatol 132(1):7–9
77. Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the
Keap1-Nrf2 pathway. Arch Toxicol 85(4):241–272
78. Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO et al (2006)
Inhibition of 7,12-Dimethylbenz(a)anthracene-induced skin tumor-
igenesis in C57BL/6 mice by sulforaphane is mediated by nuclear
factor E2-related factor 2. Cancer Res 66(16):8293–8296
79. Rundhaug JE, Fischer SM (2008) Cyclo-oxygenase-2 plays a crit-
ical role in UV-induced skin carcinogenesis. Photochem Photobiol
84(2):322–329
80. Ciolino HP, Daschner PJ, Yeh GC (1998) Resveratrol inhibits
transcription of CYP1A1 in vitro by preventing activation of the
aryl hydrocarbon receptor. Cancer Res 58(24):5707–5712
81. Palermo CM, Hernando JI, Dertinger SD, Kende AS, Gasiewicz TA
(2003) Identification of potential aryl hydrocarbon receptor antago-
nists in green tea. Chem Res Toxicol 16(7):865–872
82. Aziz MH, Reagan-Shaw S, Wu J, Longley BJ, Ahmad N (2005)
Chemoprevention of skin cancer by grape constituent resveratrol:
relevance to human disease? FASEB J 19(9):1193–1195
83. Lu YP, Lou YR, Xie JG, Peng QY, Liao J, Yang CS et al (2002)
Topical applications of caffeine or (−)-epigallocatechin gallate
(EGCG) inhibit carcinogenesis and selectively increase apoptosis
in UVB-induced skin tumors in mice. Proc Natl Acad Sci U S A
99(19):12455–12460
84. Sun SY, Hail N Jr, Lotan R (2004) Apoptosis as a novel target for
cancer chemoprevention. J Natl Cancer Inst 96(9):662–672
85. Rosette C, Karin M (1996) Ultraviolet light and osmotic stress:
activation of the JNK cascade through multiple growth factor and
cytokine receptors. Science 274(5290):1194–1197
86. Tran QT, Kennedy LH, Leon CS, Bodreddigari S, Goodwin SB,
Sutter CH et al (2012) EGFR regulation of epidermal barrier func-
tion. Physiol Genomics 44(8):455–469
87. Sutter CH, Yin H, Li Y, Mammen JS, Bodreddigari S, Stevens G
et al (2009) EGF receptor signaling blocks aryl hydrocarbon
689
receptor-mediated transcription and cell differentiation in human
epidermal keratinocytes. Proc Natl Acad Sci U S A 106(11):
4266–4271
88. Takagi S, Tojo H, Tomita S, Sano S, Itami S, Hara M et al (2003)
Alteration of the 4-sphingenine scaffolds of ceramides in
keratinocyte-specific Arnt-deficient mice affects skin barrier func-
tion. J Clin Invest 112(9):1372–1382
89. Matsue H, Cruz PD Jr, Bergstresser PR, Takashima A (1992)
Cytokine expression by epidermal cell subpopulations. J Invest
Dermatol 99(5):42S–45S
90. Williams IR, Kupper TS (1996) Immunity at the surface: homeo-
static mechanisms of the skin immune system. Life Sci
58(18):1485–1507
91. Lai ZW, Pineau T, Esser C (1996) Identification of dioxin-
responsive elements (DREs) in the 5′ regions of putative dioxin-
inducible genes. Chem Biol Interact 100(2):97–112
92. Henley DV, Bellone CJ, Williams DA, Ruh MF (2004) MAPK
signaling pathways modulate IL-1beta expression in human
keratinocytes. Arch Biochem Biophys 424(1):112–118
93. Tsuji G, Takahara M, Uchi H, Takeuchi S, Mitoma C, Moroi Y et al
(2011) An environmental contaminant, benzo(a)pyrene, induces
oxidative stress-mediated interleukin-8 production in human
keratinocytes via the aryl hydrocarbon receptor signaling pathway.
J Dermatol Sci 62(1):42–49
94. Carvajal-Gonzalez JM, Roman AC, Cerezo-Guisado MI, Rico-
Leo EM, Martin-Partido G, Fernandez-Salguero PM (2009)
Loss of dioxin-receptor expression accelerates wound healing
in vivo by a mechanism involving TGF{beta}. J Cell Sci 122(Pt 11):
1823–1833
95. Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P,
Romani N et al (2005) Dynamics and function of Langerhans cells
in vivo: dermal dendritic cells colonize lymph node areas distinct
from slower migrating Langerhans cells. Immunity 22(5):643–654
96. Bennett CL, van Rijn E, Jung S, Inaba K, Steinman RM,
Kapsenberg ML et al (2005) Inducible ablation of mouse
Langerhans cells diminishes but fails to abrogate contact hypersen-
sitivity. J Cell Biol 169(4):569–576
97. Zhao X, Deak E, Soderberg K, Linehan M, Spezzano D, Zhu J et al
(2003) Vaginal submucosal dendritic cells, but not Langerhans cells,
induce protective Th1 responses to herpes simplex virus-2. J Exp
Med 197(2):153–162
98. Allan RS, Smith CM, Belz GT, van Lint AL, Wakim LM, Heath
WR et al (2003) Epidermal viral immunity induced by CD8alpha +
dendritic cells but not by Langerhans cells. Science 301(5641):
1925–1928
99. Puhvel SM, Sakamoto M, Reisner RM (1989) Effect of TCDD on
the density of Langerhans cells in murine skin. Toxicol Appl
Pharmacol 99(1):72–80
100. Kadow S, Jux B, Zahner SP, Wingerath B, Chmill S, Clausen BE
et al (2011) Aryl hydrocarbon receptor is critical for homeostasis of
invariant gamma}{delta T cells in the murine epidermis. J Immunol
187(6):3104–3110
101. Kadow S, Jux B, Chmill S, Esser C (2010) Small molecules as
friends and foes of the immune system. Future Med Chem 1(9):
1583–1591
102. Merk HF, Baron JM, Heise R, Fritsche E, Schroeder P, Abel J et al
(2006) Concepts in molecular dermatotoxicology. Exp Dermatol
15(9):692–704
103. Ito T, Inouye K, Nohara K, Tohyama C, Fujimaki H (2008) TCDD
exposure exacerbates atopic dermatitis-related inflammation in NC/
Nga mice. Toxicol Lett 177(1):31–37
104. Vogel CF, Matsumura F (2009) A new cross-talk between the aryl
hydrocarbon receptor and RelB, a member of the NF-kappaB fam-
ily. Biochem Pharmacol 77(4):734–745
105. Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K
et al (2009) Aryl hydrocarbon receptor in combination with Stat1
690
regulates LPS-induced inflammatory responses. J Exp Med
206(9):2027–2035
106. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L,
Renauld JC et al (2008) The aryl hydrocarbon receptor links
TH17-cell-mediated autoimmunity to environmental toxins. Nature
453(7191):106–109
107. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E
et al (2008) Control of T(reg) and T(H)17 cell differentiation by the
aryl hydrocarbon receptor. Nature 453(7191):65–71
108. Ito M, Ogawa K, Takeuchi K, Nakada A, Heishi M, Suto H et al
(2004) Gene expression of enzymes for tryptophan degradation
pathway is upregulated in the skin lesions of patients with atopic
dermatitis or psoriasis. J Dermatol Sci 36(3):157–164
109. Voorhis MV, Fechner JH, Zhang X, Mezrich JD (2012) The Aryl
hydrocarbon receptor: a novel target for immunomodulation in
organ transplantation. Transplantation
110. Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D et al
(2010) The aryl hydrocarbon receptor interacts with c-Maf to pro-
mote the differentiation of type 1 regulatory T cells induced by IL-
27. Nat Immunol 11(9):854–861
111. Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B, Laroni A et al
(2010) Activation of the aryl hydrocarbon receptor induces human
type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat
Immunol 11(9):846–853
112. Fujita H, Nograles KE, Kikuchi T, Gonzalez J, Carucci JA, Krueger
JG (2009) Human Langerhans cells induce distinct IL-22-producing
CD4+ T cells lacking IL-17 production. Proc Natl Acad Sci U S A
106(51):21795–21800
113. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) Identi-
fication of a human helper T cell population that has abundant
production of interleukin 22 and is distinct from T(H)-17, T(H)1
and T(H)2 cells. Nat Immunol 10(8):864–871
114. Zhang N, Pan HF, Ye DQ (2011) Th22 in inflammatory and auto-
immune disease: prospects for therapeutic intervention. Mol Cell
Biochem 353(1–2):41–46
115. Wu HY, Quintana FJ, da Cunha AP, Dake BT, Koeglsperger T,
Starossom SC et al (2011) In vivo induction of Tr1 cells via mucosal
dendritic cells and AHR signaling. PLoS One 6(8):e23618
116. Girardi M, Lewis JM, Filler RB, Hayday AC, Tigelaar RE (2006)
Environmentally responsive and reversible regulation of epidermal
barrier function by gamma delta T cells. J Invest Dermatol
126(4):808–814
117. Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M (2009)
Interleukin-17-producing gamma delta T cells selectively expand in
response to pathogen products and environmental signals. Immunity
31(2):321–330
118. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR,
Grigorieva EF et al (2011) Exogenous stimuli maintain
intraepithelial lymphocytes via aryl hydrocarbon receptor activa-
tion. Cell. doi:10.1016/j.cell.2011.09.025
119. Ebert LM, Meuter S, Moser B (2006) Homing and function of
human skin gamma delta T cells and NK cells: relevance for tumor
surveillance. J Immunol 176(7):4331–4336
120. Jameson J, Havran WL (2007) Skin gamma-delta T cell functions in
homeostasis and wound healing. Immunol Rev 215:114–122
121. Holtmeier W, Kabelitz D (2005) Gamma-delta T cells link innate
and adaptive immune responses. Chem Immunol Allergy 86:151–
183
122. Laggner U, Di MP, Perera GK, Hundhausen C, Lacy KE, Ali N et al
(2011) Identification of a novel proinflammatory human skin-
homing Vgamma9Vdelta2 T cell subset with a potential role in
psoriasis. J Immunol 187(5):2783–2793
123. Cai Y, Fleming C, Yan J (2012) New insights of T cells in the
pathogenesis of psoriasis. Cell Mol Immunol 9(4):302–309
124. Prud’homme GJ (2012) Cancer stem cells and novel targets for
antitumor strategies. Curr Pharm Des 18(19):2838–2849
Semin Immunopathol (2013) 35:677–691
125. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S
et al (2011) An endogenous tumor-promoting ligand of the human
aryl hydrocarbon receptor. Nat Geosci 478(7368):197–203
126. Ma Q (2011) Influence of light on aryl hydrocarbon receptor
signaling and consequences in drug metabolism, physiology,
and disease. Expert Opin Drug Metab Toxicol 7(10):1267–
1293
127. Korkina LG, Pastore S, Dellambra E, De LC (2012) New molecular
and cellular targets for chemoprevention and treatment of skin
tumors by plant polyphenols: a critical review. Curr Med Chem
128. Platzer B, Richter S, Kneidinger D, Waltenberger D, Woisetschlager
M, Strobl H (2009) Aryl hydrocarbon receptor activation inhibits
in vitro differentiation of human monocytes and Langerhans den-
dritic cells. J Immunol 183(1):66–74
129. Sibilano R, Frossi B, Calvaruso M, Danelli L, Betto E, Dall’Agnese
A et al (2012) The aryl hydrocarbon receptor modulates acute and
late mast cell responses. J Immunol 189(1):120–127
130. Cho YC, Zheng W, Jefcoate CR (2004) Disruption of cell–cell
contact maximally but transiently activates AhR-mediated transcrip-
tion in 10 T1/2 fibroblasts. Toxicol Appl Pharmacol 199(3):220–
238
131. Ju Q, Fimmel S, Hinz N, Stahlmann R, Xia L, Zouboulis CC (2011)
2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell dif-
ferentiation in vitro. Exp Dermatol 20(4):320–325
132. Singh KP, Casado FL, Opanashuk LA, Gasiewicz TA (2009) The
aryl hydrocarbon receptor has a normal function in the regulation of
hematopoietic and other stem/progenitor cell populations. Biochem
Pharmacol 77(4):577–587
133. Esser C, Rannug A, Stockinger B (2009) The aryl hydrocarbon
receptor and immunity. Trends Immunol 9:447–454
134. Pauly SK, Fechner JH, Zhang X, Torrealba J, Bradfield CA,
Mezrich JD (2012) The aryl hydrocarbon receptor influences trans-
plant outcomes in response to environmental signals. Toxicol En-
viron Chem 94(6):1175–1187
135. Schallreuter KU, Salem MA, Gibbons NC, Martinez A, Slominski
R, Ludemann J et al (2012) Blunted epidermal L -tryptophan me-
tabolism in vitiligo affects immune response and ROS scavenging
by Fenton chemistry, part 1: epidermal H2O2/ONOO(−)-mediated
stress abrogates tryptophan hydroxylase and Dopa decarboxylase
activities, leading to low serotonin and melatonin levels. FASEB J
26(6):2457–2470
136. Kramer HJ, Podobinska M, Bartsch A, Battmann A, Thoma W,
Bernd A et al (2005) Malassezin, a novel agonist of the aryl
hydrocarbon receptor from the yeast Malassezia furfur, induces
apoptosis in primary human melanocytes. Chembiochem
6(5):860–865
137. Gaitanis G, Magiatis P, Stathopoulou K, Bassukas ID, Alexopoulos
EC, Velegraki A et al (2008) AhR ligands, malassezin, and
indolo[3,2-b]carbazole are selectively produced by Malassezia
furfur strains isolated from seborrheic dermatitis. J Invest Dermatol
128(7):1620–1625
138. Gaido KW, Maness SC, Leonard LS, Greenlee WF (1992) 2,3,7,8-
Tetrachlorodibenzo-p-dioxin-dependent regulation of transforming
growth factors-alpha and -beta 2 expression in a human keratinocyte
cell line involves both transcriptional and post-transcriptional con-
trol. J Biol Chem 267(34):24591–24595
139. Loertscher JA, Lin TM, Peterson RE, Allen-Hoffmann BL (2002)
In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin causes
accelerated terminal differentiation in fetal mouse skin. Toxicol
Sci 68(2):465–472
140. Sutter CH, Bodreddigari S, Campion C, Wible RS, Sutter TR (2011)
2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the expression of
genes in the human epidermal differentiation complex and acceler-
ates epidermal barrier formation. Toxicol Sci 124(1):128–137
141. Loertscher JA, Sattler CA, Allen-Hoffmann BL (2001) 2,3,7,8-
Tetrachlorodibenzo-p-dioxin alters the differentiation pattern of
Semin Immunopathol (2013) 35:677–691
human keratinocytes in organotypic culture. Toxicol Appl
Pharmacol 175(2):121–129
142. Villano CM, Murphy KA, Akintobi A, White LA (2006) 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) induces matrix metallopro-
teinase (MMP) expression and invasion in A2058 melanoma cells.
Toxicol Appl Pharmacol 210(3):212–224
143. Naldi L, Chatenoud L, Linder D, Belloni FA, Peserico A, Virgili AR
et al (2005) Cigarette smoking, body mass index, and stressful life
691
events as risk factors for psoriasis: results from an Italian case–
control study. J Invest Dermatol 125(1):61–67
144. D’Cruz D (2000) Autoimmune diseases associated with drugs,
chemicals and environmental factors. Toxicol Lett 112–113:421–432
145. Rieber N, Belohradsky BH (2010) AHR activation by tryptophan-
pathogenic hallmark of Th17-mediated inflammation in eosinophil-
ic fasciitis, eosinophilia-myalgia-syndrome, and toxic oil syn-
drome? Immunol Lett 128(2):154–155
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