The Journal of Experimental Medicine
BRIEF DEFINITIVE REPORT
JEM © The Rockefeller University Press $15.00
Vol. 204, No. 2, February 19, 2007 253–258 www.jem.org/cgi/doi/10.1084/jem.20062211
Atopic diseases, including asthma, atopic der-
matitis (AD), and allergic rhinitis, are associated
with a genetic predisposition to develop pro-
infl ammatory immune responses to harmless
components of the environment. These aber-
rant immune responses are characterized by the
development of CD4+ T lymphocytes produc-
ing Th2 cytokines (IL-4, IL-5, and IL-13) and
inducing the production of IgE antibodies. The
important roles of Th2 lymphocytes and IgE-
dependent activation of tissue mast cells (MCs)
in acute and chronic infl ammation characteriz-
ing atopic diseases have been well established in
clinical and animal models. The allergic infl am-
mation involves the accumulation of a cellular
infi ltrate in the airway mucosa or the skin con-
sisting of eosinophils, CD4+ T cells, MCs,
DCs, and basophils (1, 2).
Compelling evidence was recently provided
that thymic stromal lymphopoietin (TSLP), an
epithelial cell–derived cytokine, may have a
determinant role in the initiation and mainte-
nance of the allergic immune response (3, 4).
TSLP was initially shown to activate and
instruct human CD11c+ DCs to promote the
diff erentiation of naive CD4+ T cells into Th2
proinfl ammatory eff ectors, defi ned by the pro-
duction of high levels of pro-allergic cytokines
IL-4, IL-5, IL-13, TNF, and low levels of IL-
10 (5, 6). The role of TSLP in allergic diseases
was subsequently supported by the fi ndings
that it was specifi cally overexpressed in the
acute and chronic lesions of AD patients and
in the bronchi of asthmatic patients, where its
level of expression correlated with the sever-
ity of the disease (3, 7). The ability of TSLP
to act as the initiating cytokine at the top of a
chain of immunological events that lead to the
atopic syndrome was formally demonstrated
in animal models (8–10). Overexpression of
the TSLP gene specifi cally in airway epithelial
cells or keratinocytes led to asthma- and AD-
like diseases, respectively (9, 10). Moreover,
increased expression of TSLP in the keratino-
cytes of mice genetically defi cient in retinoic
acid receptor or treated by topical application
Thymic stromal lymphopoietin is released
by human epithelial cells in response
to microbes, trauma, or infl ammation
and potently activates mast cells
Zoulfi a Allakhverdi,1 Michael R. Comeau,4 Heidi K. Jessup,4
Bo-Rin Park Yoon,4 Avery Brewer,4 Suzanne Chartier,3 Nicole Paquette,3
Steven F. Ziegler,5 Marika Sarfati,2 and Guy Delespesse1
1Laboratory on Allergy, 2Laboratory on Immunoregulation, CHUM Research Center, and 3Dermatology Service,
Notre-Dame Hospital, Montreal, Quebec H2L 4M1, Canada
4Infl ammation Research, Amgen Inc., Seattle, WA 98119
5Department of Immunology, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA 98101
Compelling evidence suggests that the epithelial cell–derived cytokine thymic stromal
lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell–
mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate
allergic infl ammation in the absence of T lymphocytes and immunoglobulin E antibodies via
the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor
necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast
cells (MCs). We next report that TSLP is released by primary epithelial cells in response to
certain microbial products, physical injury, or infl ammatory cytokines. Direct epithelial
cell–mediated, TSLP-dependent activation of MCs may play a central role in “intrinsic”
forms of atopic diseases and explain the aggravating role of infection and scratching in
The online version of this article contains supplemental material.
254 EPITHELIAL CELL–DERIVED TSLP ACTIVATES MAST CELLS | Allakhverdi et al.
of vitamin D3 was correlated with the occurrence of typi-
cal immunological and histological features of AD (11, 12).
However, the fi ndings that induction of experimental der-
matitis or asthma can occur in TSLP-transgenic mice lacking
T cells (TCRβ−/− or RAG−/−) demonstrated that bronchial
or cutaneous allergic diseases can occur in T cell– and IgE-
defi cient animals (9–11). These fi ndings suggested to us that
TSLP may directly activate eff ector cells of the innate
immune system like MCs, which are known to play an impor-
tant role in the pathogenesis of atopic diseases (13, 14). Here,
we report that TSLP released by primary epithelial cells in
response to clinically relevant stimuli directly activates hu-
man MCs inducing the production of high levels of Th2 pro-
infl ammatory cytokines.
RESULTS AND DISCUSSION
Human MCs express functional receptor for TSLP
The expression of each chain of TSLP receptor complex, i.e.,
the TSLP-binding chain (TSLP-R) and the IL-7Rα chain
(15), was fi rst examined on progenitor-derived MCs at the
mRNA and protein levels. TSLP-R mRNA was expressed
on MCs but not on T cells used as a control. IL-7Rα was ex-
pressed at lower levels on MCs than on T cells. Expression of
TSLP receptor complex was indicated by double labeling
with mAb to c-kit in tandem with mAbs to either TSLP-R
or IL-7Rα (Fig. 1 A). Importantly, TSLP receptor was also
expressed in vivo on MCs infi ltrating the bronchial mucosa
of asthmatic patients as revealed by immunostaining of biopsy
specimen (Fig. 1 B). Initial observations revealed that only
IL-1 but not TNF, IL-4, or IL-6 exerted a permissive eff ect
on the activation of MCs by TSLP as illustrated by the pro-
duction of IL-5 (Fig. 1 C). Moreover, the response to TSLP
plus IL-1 was further enhanced by TNF but not by IL-4 or
IL-6. All the in vitro–generated MC lines examined in this
study (n = 19) responded to TSLP in the presence of IL-1/
TNF, regardless of whether they were derived from the
blood of atopic or nonatopic adults or umbilical cord blood.
The response of MCs to TSLP was dose dependent (Fig. 1 D);
it was already detectable after 6 h of culture and reached pla-
teau at 24 h (Fig. 1 E). This response was TSLP specifi c and
mediated by TSLP-R. Indeed, (a) it was specifi cally sup-
pressed by neutralizing mAb to TSLP or TSLP-R (Fig. 1,
F and G), and (b) the inhibitory activities of these mAbs were
TSLP specifi c in that they had no eff ect on the production
of CCL2, which was highly induced by stimulation with
IL-1/TNF in the absence of TSLP (Fig. S1 A, available at
TSLP stimulation of MCs induces cytokine production
but not mediator release
Typically, IgE-dependent MC activation results in the libera-
tion of granule-associated mediators such as histamine and
tryptase, the synthesis of lipid mediators such as PGD2 and
LTC4, and the synthesis of a wide spectrum of cytokines
and chemokines. MC activation is not a “yes or no” pheno-
menon, and similar to several other MC activators (for review
see reference 16), TSLP did not induce MC degranulation
or the release of lipid mediators (Fig. S2, available at
even when used at various concentrations with or without
IL-1/TNF. In contrast, very high levels of the proinfl ammatory
cytokines/chemokines IL-5, IL-13, IL-6, GM-CSF, CXCL8,
and CCL1 were released after 24 h of MC stimulation by TSLP
in the presence of IL-1/TNF (Fig. 2). Regardless of the ex-
perimental conditions, the following cytokines/chemokines,
Figure 1. Human MCs expressed functional receptor for TSLP.
(A) TSLP-R and IL-7Rα chain expression was determined at mRNA on MCs
and peripheral blood T cells (mean ± SEM of eight experiments on differ-
ent MC lines) and protein levels. (B) Tissue sections from the bronchial
mucosa of asthmatic patients were stained with TSLP-R mAb using an
HRP system (brown) and Astra Blue (blue) for the identifi cation of MCs.
(C) MCs were stimulated with TSLP alone or together with different in-
fl ammatory cytokines. The 24-h culture supernatants were tested for their
content in IL-5. One representative of three experiments is shown; mean ±
SD of triplicates. (D) MCs were stimulated with varying concentrations of
TSLP in the presence of 10 ng/ml IL-1 and 25 ng/ml TNF. One representa-
tive of three experiments is shown; mean ± SD of triplicates. (E) Time
course of cytokine production by MCs stimulated with 10 ng/ml IL-1β/
TNF and TSLP. Mean ± SEM (n = 5). (F and G) MCs were stimulated in the
presence of neutralizing mAb to TSLP (F) or TSLP-R (G) and isotype control
IgG (each at 10 μg/ml). One representative of three experiments is shown;
mean ± SD of triplicates.
JEM VOL. 204, February 19, 2007
BRIEF DEFINITIVE REPORT
including IL-4, IL-9, IL-12, IL-15, IFN-γ, CXCL10,
CCL24, CCL17, CCL13, CCL22, and CCL5, were either
undetectable or present at very low levels (<70 pg/ml).
Stimulation of MCs with IL-1/TNF induced the release of
high levels of CCL2 and CCL3, and this was not aff ected by
TSLP (CCL2: 3,512 ± 346 pg/ml vs. 3,912 ± 669 pg/ml
with TSLP; CCL3: 3,921 ± 725 pg/ml vs. 3,415 ± 483 pg/ml
with TSLP). Collectively, these data indicated that in in-
fl ammatory conditions mimicked by the presence of IL-1
and TNF, TSLP is a potent activator of MCs leading to the
production of very high levels of proinfl ammatory Th2
cytokines and chemokines that are reportedly suffi cient to
induce and maintain an allergic phenotype. For instance, the
perfusion of IL-13 induces an asthma-like phenotype charac-
terized by eosinophilic infl ammation, bronchial hyperreac-
tivity, and airway remodeling (17). Given the important role
of TNF in severe asthma (18), it is of note that this cytokine
was released at high levels by MCs stimulated with IL-1 and
TSLP (not depicted). The proinfl ammatory activity of TSLP
was further indicated by its suppressive activity on the pro-
duction of TGF-β. This fi nding together with the observa-
tion that TGF-β inhibits the response to TSLP (Fig. S3)
suggests a negative regulatory feedback between these two
cytokines. In contrast to TGF-β, the production of IL-10
was enhanced by TSLP and exogenous IL-10 did not aff ect
the MC response to TSLP (not depicted). IL-10 is overex-
pressed in the lesional skin of AD patients (19) where it in-
hibits the production of antimicrobial peptides, thereby
contributing to the microbial colonization of the skin (20).
Because IgE/anti-IgE–stimulated MCs reportedly expressed
TSLP mRNA (5), we have examined TSLP expression in
response to IL-1/TNF used alone or together with exoge-
nous TSLP. TSLP was not induced in these conditions as re-
vealed by: (a) the absence of TSLP protein in the culture
supernatants of IL-1/TNF-stimulated MCs (<7 pg/ml),
(b) the lack of eff ect of blocking anti-TSLP mAb on chemo-
kine production by IL-1/TNF-stimulated MCs, and (c)
quantitative real-time RT-PCR analysis of TSLP mRNA
expression (Fig. S1, A and B). The potential clinical signifi -
cance of the fi ndings that TSLP-stimulated MCs produce
high levels of proinfl ammatory Th2 cytokines and chemo-
kines is supported by the recently reemphasized concept that
MCs have a central role in the development and maintenance
of allergic diseases (for review see reference 13).
Human epithelial cells produce biologically active TSLP
Given that overexpression of TSLP in the airway epithelial
cells induces experimental asthma (9), and that TSLP mRNA
is overexpressed in the bronchial mucosa of asthmatic pa-
tients (7), we attempted to identify stimuli capable of induc-
ing TSLP production by human airway epithelial cells. To
this end, primary small airway epithelial cells (SAECs) were
stimulated with: (a) a cocktail of IL-1 and TNF to mimic
the infl ammatory microenvironment, and (b) bacterial pep-
tidoglycan (PGN) and TLR ligands such as lipoteichoic acid
(LTA) from Bacillus subtilis, poly I:C (mimicking viral double-
stranded RNA), LPS, imiquimod, and CpG. TSLP was pro-
duced only in response to the infl ammatory cytokines, PGN,
LTA, and poly I:C (Fig. 3 A and Fig. S4, which is available at
The failure of SAEC to respond to LPS, imiquimod, and
CpG was explained by the lack of expression of the corre-
sponding TLR’s mRNA (Fig. 3 B). The supernatant fl uids
of activated SAECs promoted the TSLP-dependent pro-
liferation of a BAF cell line transfected with the human TSLP
receptor complex (Fig. 3 C). Moreover, the low levels of
TSLP present in these culture supernatants were suffi cient
when used together with IL-1/TNF to induce IL-13 and
IL-5 production from MCs (Fig. 3, D–F, and not depicted).
Native SAEC-derived TSLP was active at much lower con-
centrations (50–100 pg/ml; see Fig. 3 A) than recombinant
TSLP (10 ng/ml) used as a positive control (Fig. 3 D). This
fi nding suggested that activated SAECs may produce addi-
tional factors that act to co-stimulate the response of MCs
to TSLP; alternatively, it could refl ect a diff erence in the
Figure 2. TSLP-stimulated secretion of cytokines and chemokines
by MCs. Cytokine (A) and chemokine (B) secretion by MCs (105 cells/ml)
stimulated for 24 h with 10 ng/ml IL-1β/TNF or/and TSLP was assessed by
ELISA. Mean ± SEM (n = 11).
256 EPITHELIAL CELL–DERIVED TSLP ACTIVATES MAST CELLS | Allakhverdi et al.
intrinsic activity of native and recombinant TSLP. It is of note
that SAECs stimulated with cytokines, PGN, or polyI:C did
not produce detectable IL-5 or IL-13. Moreover, PGN or
polyI:C induced the production of very low (<70 pg/ml)
or undetectable levels of IL-5 or IL-13 by MCs, even when
used together with IL-1/TNF. The observation that bacterial
and viral products induce TSLP production by SAEC may be
related to the well-documented aggravating role of infection
in allergic as well as intrinsic bronchial asthma. For exam-
ple, 60–80% of asthma exacerbations in children and adults
are caused by rhinovirus infection (21). Rhinoviruses, like
several other single-stranded RNA viruses, synthesize double-
stranded RNA during their replication, thereby engaging
TLR3 and initiating signaling cascades leading to cytokine
production (22). The up-regulation of TSLP by bacterial
products is, however, not restricted to airway epithelial cells
as it has been shown in intestinal epithelial cells (23). TSLP
activation of MCs may also contribute to the aggravation of
AD resulting from skin colonization by Staphylococcus aureus
(1). Thus, certain bacterial, viral, and nonspecifi c infl amma-
tory stimuli (IL-1/TNF) may activate airway epithelial cells
to produce TSLP in suffi cient amounts to stimulate MCs and
thereby initiate and/or aggravate allergic infl ammation.
MC activation by skin-derived TSLP
Because TSLP protein is reportedly overexpressed at the le-
sional sites of AD (3), we examined the possible involvement
of TSLP-induced MC activation in this disease. To this end,
biopsy fragments of lesional and nonlesional skin from AD
patients were examined for their ability to directly stimulate
MCs in co-culture experiments. As seen in Fig. 4 A, lesional skin
induced IL-13 production by MCs in a TSLP-dependent
manner, whereas nonlesional skin from the same patients
was less active. Moreover, TSLP mRNA levels were higher
in biopsy fragments from lesional than nonlesional skin
(Fig. 4 B). The fi nding that nonlesional skin was active on
MCs led us to test whether TSLP production was a feature of
atopy or was induced by the physical trauma of the skin re-
sulting from the biopsy. The latter possibility was supported
by the fi nding that skin fragments of normal individuals re-
leased TSLP protein after 24 h of culture in suffi cient quan-
tities to stimulate MCs (Fig. 4 C). No such activity was
elicited by supernatant fl uids collected after 1 h of skin cul-
ture. Because normal skin reportedly does not express detect-
able TSLP protein (3), the data suggest that TSLP was induced
during the culture of skin explants. This view was supported
by the fi nding of increasing TSLP mRNA and protein ex-
pression over time in the skin cultures (Fig. 4, D and E). A
similar result was obtained in experiments examining TSLP
mRNA and protein expression over time in mouse skin
punch biopsies (not depicted). The production of TSLP to-
gether with several proinfl ammatory cytokines after physical
trauma may account for the aggravating role of scratching in
atopic eczema (1).
An emerging hypothesis regarding asthma and AD is that
they are epithelial cell diseases initiated by the epithelial cells
themselves via the production of TSLP (3). In the present
study we have identifi ed several clinically relevant stimuli
leading to TSLP production by primary human airway and
skin epithelial cells. We have further shown that these stimu-
lated epithelial cells release TSLP in suffi cient amounts to
activate, in synergy with IL-1/TNF, MCs to produce high
levels of Th2 cytokines. These fi ndings provide a possible
mechanism to account for the induction of atopic-like dis-
eases in T cell– and IgE-defi cient mice expressing a TSLP
transgene or submitted to topical application of vitamin
D3 on the skin (9, 11). Direct epithelial cell–mediated and
TSLP-dependent activation of MCs may be implicated in
the initiation and perpetuation of so-called “intrinsic” asthma
or eczema in ?20–30% of patients (24). Such patients have
normal serum IgE concentration and negative skin prick test
Figure 3. Induction of TSLP production by primary human airway
epithelial cells. (A) SAECs were stimulated as indicated, and the 48-h
culture supernatants were tested for their content in TSLP by ELISA. Mean ±
SEM (n = 5). (B) Expression of the indicated TLR mRNA in SAECs was
determined by real-time PCR. (C) BAF cells (104 cells/well) expressing the
human TSLP-R and IL-7Rα chains were cultured in the presence of SAEC
supernatants and in the presence or absence of neutralizing anti-TSLP
mAb, and their proliferation was assessed after 3 d. One representative of
three experiments is shown; mean ± SD of triplicates. (D–F) MCs were
cultured in the presence or absence of supernatants of SAECs (50% vol/
vol) described in A that were obtained upon stimulation with IL-1α/TNF
(D), PGN (E), or polyI:C (F). IL-13 and IL-5 (not depicted) were measured
after 24 h of MC stimulation. Mean ± SEM of four to fi ve experiments.
JEM VOL. 204, February 19, 2007
BRIEF DEFINITIVE REPORT
toward allergens; however, their infl ammatory lesions are
indistinguishable from those observed in patients with clas-
sical IgE-dependent “extrinsic” forms of the diseases (25).
The same mechanism may also explain why in infants the
eczematous skin lesions often start in the absence of specifi c
IgE antibodies, implicating that IgE sensitization may occur
after the eczema (24).
Together with earlier studies, the present data may be
taken to suggest that TSLP induces and/or perpetuates aller-
gic diseases by acting on the two main sentinels of the innate
immune system, i.e., DCs and MCs colocalized at the epithe-
MATERIALS AND METHODS
MC cultures. All studies were approved by the ethics committee of CHUM
Research Center. Human peripheral blood– or cord blood–derived CD34+
progenitor cells were isolated and cultured as described previously (26). After
10–12 wk of culture, >98% of cells were stained for c-kit (Becton Dickinson),
FcεRI (eBioscience), and tryptase (Chemicon). 2 × 104/0.2 ml MCs were
cultured in 96-well fl at-bottom plates for 24 h in the presence of exogenous
cytokines/neutralizing antibodies as indicated. The antibodies used include:
anti–IL-7Rα (R&D Systems); anti–TSLP-R (M505; Amgen); anti-TSLP
(M385; Amgen); anti–IL-10 (American Type Culture Collection). Recom-
binant cytokines included: IL-1β, TNF (R&D Systems), and recombinant
Assessment of mediator, 훃-hexosaminidase, cytokine, and chemo-
kine release. MCs were incubated for 30 min for histamine and 90 min for
PGD2 and LTC4, as well as release with cytokines or PMA/ionomycin as a
positive control, and ELISA was performed (Immunotech and Cayman
Chemical) according to the manufacturers’ instructions. β-Hexosaminidase
release was analyzed as described previously (27). IL-4, IL-5, IL-6, CXCL8,
IL-9, IL-10, IL-12, IL-13, IL-15, CCL24, CCL1, IFN-γ, CXCL10, GM-
CSF, CCL22, CCL3, CCL2, CCL13, CCL5, CCL17, and TGF-β were
examined in supernatants harvested after 24 h of MC activation via com-
mercial kits. All assays were conducted in triplicates.
Real-time quantitative PCR. RNA was isolated with RNeasy Mini kit
(QIAGEN). cDNA synthesis was performed using ABI fi rst strand cDNA
synthesis kit. Quantitative real-time PCR was performed via a TaqMan using
ABI gene expression assays. HPRT was used as a control for cDNA input.
Activation of primary SAECs. Primary SAECs (Clonetics) were grown
to confl uence and stimulated in the presence of 25 ng/ml TNF/10 ng/ml
IL-1α, 100 μg/ml PGN from S. aureus, LTA from 2 μg/ml B. subtilis,
50 μg/ml polyI:C, 1 μg/ml LPS, 10 μg/ml imiquimod, or 5 μM CpG.
Proliferation assay. BAF cells stably expressing the human TSLP-R and
IL-7Rα chains were cultured with SAEC supernatants in the presence or
absence of neutralizing anti-TSLP antibody for 3 d, and proliferation was as-
sessed by CyQUANT Cell Proliferation Assay kit (Invitrogen) according to
the manufacturer’s instructions.
MCs and skin explant co-cultures. MCs were directly co-cultured with
lesional and nonlesional skin fragments from AD patients for 24 h in the
presence or absence of exogenous cytokines/neutralizing antibodies as indi-
cated. Supernatants of skin explants from normal individuals undergoing
plastic surgery were added to MCs in the presence or absence of exogenous
cytokines/neutralizing antibodies as indicated.
Statistical analysis. Student’s paired t test and ANOVA (Tukey-Kramer
Multiple Comparisons test) were used to determine the statistical signifi -
cance of the data.
Online supplemental material. Fig. S1 shows the lack of eff ect of anti-
TSLP mAb on MC response to cytokines and on expression of TSLP mRNA.
Figure 4. MC activation by skin-derived TSLP. (A) MCs were cultured
with or without lesional or nonlesional skin fragments from AD patients in
the presence of IL-1β/TNF with or without neutralizing mAb to TSLP. IL-13
and IL-5 (not depicted) were measured in the supernatants after 24 h of
culture. (B) TSLP mRNA was assessed in the lesional and nonlesional skin of
AD patients by real-time PCR. (C) Skin explants from nonallergic patients
undergoing plastic surgery were minced and cultured for 24 h. Their cell-
free culture supernatants (50% vol/vol) were used to stimulate MCs in the
presence of IL-1β/TNF with or without mAb to TSLP and TSLP-R or isotype
control. IL-13 was measured after 24 h of culture. One representative of
three experiments is shown; mean ± SD of triplicates. (D) TSLP mRNA was
assessed on freshly isolated or cultured for 24-h skin explants. (E) TSLP
protein was measured in the supernatant fl uids of these cultures. One
representative of three experiments is shown; mean ± SD of triplicates.
258 EPITHELIAL CELL–DERIVED TSLP ACTIVATES MAST CELLS | Allakhverdi et al. Download full-text
Fig. S2 illustrates the failure of TSLP to stimulate MC degranulation and
eicosanoid production. Fig. S3 illustrates the suppressive eff ect of TGF-β
on TSLP response, and Fig. S4 shows the induction of TSLP production by
SAECs in response to specifi c TLR2 ligand. The online supplemental material
is available at http://www.jem.org/cgi/content/full/jem.20062211/DC1.
We would like to thank Dr. Y.J. Liu for his critical review of the manuscript and
also the group of nurses and obstetricians at St-Luc Hospital (Montreal, Quebec,
Canada) for providing us with umbilical cord blood. Helpful advice of Nobuyasu
Baba to grow MCs is well appreciated.
This work was supported in part by a Canadian Institute of Health Research
grant MOP 103957.
M.R. Comeau, H.K. Jessup, B.-R.P. Yoon, and A. Brewer are Amgen shareholders.
All other authors have no confl icting fi nancial interests.
Submitted: 16 October 2006
Accepted: 27 December 2006
R E F E R E N C E S
1. Leung, D.Y., M. Boguniewicz, M.D. Howell, I. Nomura, and Q.A.
Hamid. 2004. New insights into atopic dermatitis. J. Clin. Invest.
2. Kay, A.B. 2006. The role of T lymphocytes in asthma. Chem. Immunol.
3. Liu, Y.J. 2006. Thymic stromal lymphopoietin: master switch for aller-
gic infl ammation. J. Exp. Med. 203:269–273.
4. Ziegler, S.F., and Y.J. Liu. 2006. Thymic stromal lymphopoietin in
normal and pathogenic T cell development and function. Nat. Immunol.
5. Soumelis, V., P.A. Reche, H. Kanzler, W. Yuan, G. Edward, B.
Homey, M. Gilliet, S. Ho, S. Antonenko, A. Lauerma, et al. 2002.
Human epithelial cells trigger dendritic cell mediated allergic infl amma-
tion by producing TSLP. Nat. Immunol. 3:673–680.
6. Ito, T., Y.H. Wang, O. Duramad, T. Hori, G.J. Delespesse, N.
Watanabe, F.X. Qin, Z. Yao, W. Cao, and Y.J. Liu. 2005. TSLP-
activated dendritic cells induce an infl ammatory T helper type 2 cell
response through OX40 ligand. J. Exp. Med. 202:1213–1223.
7. Ying, S., B. O’Connor, J. Ratoff , Q. Meng, K. Mallett, D. Cousins,
D. Robinson, G. Zhang, J. Zhao, T.H. Lee, and C. Corrigan. 2005.
Thymic stromal lymphopoietin expression is increased in asthmatic air-
ways and correlates with expression of Th2-attracting chemokines and
disease severity. J. Immunol. 174:8183–8190.
8. Al-Shami, A., R. Spolski, J. Kelly, A. Keane-Myers, and W.J. Leonard.
2005. A role for TSLP in the development of infl ammation in an asthma
model. J. Exp. Med. 202:829–839.
9. Zhou, B., M.R. Comeau, T. De Smedt, H.D. Liggitt, M.E. Dahl, D.B.
Lewis, D. Gyarmati, T. Aye, D.J. Campbell, and S.F. Ziegler. 2005.
Thymic stromal lymphopoietin as a key initiator of allergic airway in-
fl ammation in mice. Nat. Immunol. 6:1047–1053.
10. Yoo, J., M. Omori, D. Gyarmati, B. Zhou, T. Aye, A. Brewer, M.R.
Comeau, D.J. Campbell, and S.F. Ziegler. 2005. Spontaneous atopic
dermatitis in mice expressing an inducible thymic stromal lympho-
poietin transgene specifi cally in the skin. J. Exp. Med. 202:541–549.
11. Li, M., P. Hener, Z. Zhang, S. Kato, D. Metzger, and P. Chambon.
2006. Topical vitamin D3 and low-calcemic analogs induce thymic
stromal lymphopoietin in mouse keratinocytes and trigger an atopic der-
matitis. Proc. Natl. Acad. Sci. USA. 103:11736–11741.
12. Li, M., N. Messaddeq, M. Teletin, J.L. Pasquali, D. Metzger, and P.
Chambon. 2005. Retinoid X receptor ablation in adult mouse kerati-
nocytes generates an atopic dermatitis triggered by thymic stromal lym-
phopoietin. Proc. Natl. Acad. Sci. USA. 102:14795–14800.
13. Bradding, P., A.F. Walls, and S.T. Holgate. 2006. The role of the
mast cell in the pathophysiology of asthma. J. Allergy Clin. Immunol.
14. Imayama, S., Y. Shibata, and Y. Hori. 1995. Epidermal mast cells in
atopic dermatitis. Lancet. 346:1559.
15. Park, L.S., U. Martin, K. Garka, B. Gliniak, J.P. Di Santo, W. Muller,
D.A. Largaespada, N.G. Copeland, N.A. Jenkins, A.G. Farr, et al. 2000.
Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor:
formation of a functional heteromeric complex requires interleukin 7
receptor. J. Exp. Med. 192:659–670.
16. Galli, S.J., J. Kalesnikoff , M.A. Grimbaldeston, A.M. Piliponsky, C.M.
Williams, and M. Tsai. 2005. Mast cells as “tunable” eff ector and immu-
noregulatory cells: recent advances. Annu. Rev. Immunol. 23:749–786.
17. Wills-Karp, M. 2004. Interleukin-13 in asthma pathogenesis. Immunol.
18. Berry, M.A., B. Hargadon, M. Shelley, D. Parker, D.E. Shaw, R.H.
Green, P. Bradding, C.E. Brightling, A.J. Wardlaw, and I.D. Pavord.
2006. Evidence of a role of tumor necrosis factor alpha in refractory
asthma. N. Engl. J. Med. 354:697–708.
19. Kallmann, B.A., H. Kolb, M. Huther, S. Martin, M. Hellermann, and
E.F. Lampeter. 1996. Interleukin-10 is a predominant cytokine in atopic
dermatitis. Arch. Dermatol. 132:1133–1134.
20. Howell, M.D., N. Novak, T. Bieber, S. Pastore, G. Girolomoni, M.
Boguniewicz, J. Streib, C. Wong, R.L. Gallo, and D.Y. Leung. 2005.
Interleukin-10 downregulates anti-microbial peptide expression in
atopic dermatitis. J. Invest. Dermatol. 125:738–745.
21. Chen, Y., E. Hamati, P.K. Lee, W.M. Lee, S. Wachi, D. Schnurr, S.
Yagi, G. Dolganov, H. Boushey, P. Avila, and R. Wu. 2006. Rhinovirus
induces airway epithelial gene expression through double-stranded RNA
and IFN-dependent pathways. Am. J. Respir. Cell Mol. Biol. 34:192–203.
22. Hewson, C.A., A. Jardine, M.R. Edwards, V. Laza-Stanca, and S.L.
Johnston. 2005. Toll-like receptor 3 is induced by and mediates antiviral
activity against rhinovirus infection of human bronchial epithelial cells.
J. Virol. 79:12273–12279.
23. Rimoldi, M., M. Chieppa, V. Salucci, F. Avogadri, A. Sonzogni, G.M.
Sampietro, A. Nespoli, G. Viale, P. Allavena, and M. Rescigno. 2005.
Intestinal immune homeostasis is regulated by the crosstalk between epi-
thelial cells and dendritic cells. Nat. Immunol. 6:507–514.
24. Novak, N., and T. Bieber. 2003. Allergic and nonallergic forms of
atopic diseases. J. Allergy Clin. Immunol. 112:252–262.
25. Humbert, M., G. Menz, S. Ying, C.J. Corrigan, D.S. Robinson, S.R.
Durham, and A.B. Kay. 1999. The immunopathology of extrinsic
(atopic) and intrinsic (non-atopic) asthma: more similarities than diff er-
ences. Immunol. Today. 20:528–533.
26. Kirshenbaum, A.S., and D.D. Metcalfe. 2006. Growth of human mast
cells from bone marrow and peripheral blood-derived CD34+ pluripo-
tent progenitor cells. Methods Mol. Biol. 315:105–112.
27. Kulka, M., L. Alexopoulou, R.A. Flavell, and D.D. Metcalfe. 2004.
Activation of mast cells by double-stranded RNA: evidence for activation
through Toll-like receptor 3. J. Allergy Clin. Immunol. 114:174–182.