Expression of the type 2 receptor for cysteinyl
leukotrienes (CysLT2R) by human mast cells:
Functional distinction from CysLT1R
Elizabeth A. Mellor*, Nita Frank†, Dulce Soler†, Martin R. Hodge†, Jose M. Lora†, K. Frank Austen*‡§,
and Joshua A. Boyce*‡§¶?
*Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, and Departments of‡Medicine and¶Pediatrics, Harvard Medical
School, Boston, MA 02115;§Partners Asthma Center, Boston, MA 02115; and†Department of Immunobiology and Inflammation, Millennium
Pharmaceuticals, Inc., Cambridge, MA 02139
Contributed by K. Frank Austen, August 6, 2003
Cysteinyl leukotrienes (cysLTs) mediate vascular leakage and bron-
choconstriction through the smooth muscle-associated CysLT type
1 receptor (CysLT1R), one of at least two loosely homologous
cysLT-binding G protein-coupled receptors. We previously re-
ported that CysLT1R is expressed by cultured human mast cells
(hMCs), and that priming these cells with IL-4 enhances their
sensitivity to calcium flux and cytokine generation in response to
cys-LTs and the nucleotide ligand, uridine diphosphate (UDP),
without increasing their surface expression of CysLT1R. We now
report that hMCs express the type 2 receptor for cysLTs (CysLT2R)
as well, and that the amount of surface CysLT2R protein increases
in response to priming with IL-4. The selective function of CysLT2R
was evident based on uninhibited IL-8 secretion by IL-4-primed
hMCs stimulated with cys-LTs or UDP in the presence of the
selective CysLT1R antagonist MK571. MK571 did inhibit IL-5 gen-
eration, calcium flux, and phosphorylation of extracellular signal-
regulated kinase. IL-8 secretion was inhibited by pertussis toxin
and a selective p38 kinase inhibitor, SB203580. The CysLT2 re-
sponse may permit the cys-LTs and nucleotides generated in
infection and tissue injury to elicit IL-8 generation by hMCs,
potentially leading to neutrophilic infiltration, a characteristic of
aerosol challenge-induced late-phase responses and of sudden
death associated with asthma.
mast cells (MCs), eosinophils, basophils, and alveolar macro-
phages. In addition to potent effects on vascular smooth muscle
(1–3), cysLTs are powerful bronchoconstrictors in vivo (4, 5),
accounting for ?50% of the decrease in the forced expiratory
volume at 1 sec (FEV1) that occurs during allergen-induced
early phase airflow obstruction in individuals with allergic
asthma (6). The effects of the cysLTs are mediated through two
known receptors: the CysLT type 1 receptor (CysLT1R) which
and the CysLT type 2 receptor (CysLT2R). The cysLTs also act
on inflammatory cells, recruiting both eosinophils and neutro-
phils when instilled into the airways of human subjects (9).
Furthermore, the selective antagonism of CysLT1R decreases
both sputum and peripheral blood eosinophil counts (10), a
finding that may relate to the ability of cysLTs to induce cytokine
production by resident lung cells (11). Although CysLT2R is
coexpressed with CysLT1R on several immune cells (12–15), no
specific functions have been reported for CysLT2R.
CysLT1R and CysLT2R are only loosely homologous (38%
amino acid identity) (12, 13, 16, 17) and each also shares a
similar degree of identity (24–32%) with the purinergic (P2Y)
class of G protein-coupled receptors (GPCRs) that mediate
cellular responses to extracellular nucleotides (18). CysLT1R
and CysLT2R have different ligand affinities when expressed
heterologously. CysLT1R binds leukotriene D4(LTD4) with a
10-fold higher affinity than it binds leukotriene C4 (LTC4)
he cysteinyl leukotrienes (cysLTs) are a class of lipid inflam-
matory mediators formed from arachidonic acid by activated
(EC50? 10?9M vs. 10?8M, respectively), whereas CysLT2R
binds LTC4and LTD4equally (EC50? 10?8M) (12, 13).
We previously reported (19) that cord blood-derived human
MCs (hMCs) express CysLT1R protein and mRNA and respond
to cysLTs with a strong and sustained calcium flux that is
completely blocked by pretreatment of the cells with MK571, a
CysLT1R-selective competitive antagonist. CysLT-mediated
calcium flux is resistant to treatment with pertussis toxin (PTX),
consistent with the coupling of the CysLT1R to PTX-resistant
Gq proteins in hMCs, as reported for Xenopus oocytes trans-
fected with human CysLT1R (12). When primed with IL-4, the
sensitivity of hMCs to LTC4 is markedly enhanced (and to a
greater extent than their sensitivity to LTD4). Unexpectedly,
IL-4 priming also enhances the calcium response of hMCs to
uridine diphosphate (UDP), and UDP desensitizes the hMCs to
LTC4-induced calcium flux, but not to LTD4. Moreover, IL-4
primed hMCs (but not their unprimed replicates) secrete IL-5,
tumor necrosis factor (TNF)-?, and macrophage inflammatory
protein (MIP)-1? in response to stimulation with LTC4, LTD4,
or UDP, without undergoing exocytosis (20). Production of all
three of these cytokines by IL-4-primed hMCs in response to
cysLTs and UDP is inhibited by the calcineurin inhibitor FK506,
by the selective inhibitor of extracellular regulated kinase (ERK)
UO126, and by MK571, indicating ligand recognition by
CysLT1R or a CysLT1R-like receptor.
Because the marked IL-4-induced enhancement of the cal-
cium flux induced by LTC4and UDP did not involve changes in
surface levels of CysLT1R, and because the partial CysLT2R
agonist BAY-u9773 induced a small calcium flux in hMCs, we
hypothesized the presence of a second functional CysLTR on
hMCs. We now report that cord blood-derived hMCs constitu-
tively express CysLT2R and that IL-4 consistently up-regulates
the surface expression of CysLT2R on a fraction of hMCs. In
these hMCs, MK571 completely blocked the cysLT-initiated
calcium response and generation of IL-5 and the LTC4-induced
phosphorylation of ERK. However, MK571 did not interfere
with sustained LTC4-induced p38 mitogen-activated protein
kinase (MAPK) phosphorylation and left cysLT-and UDP-
dependent IL-8 generation unaffected. The partial CysLT2R
IL-8 is a ‘‘signature’’ cytokine of CysLT2R-mediated hMC
activation. Moreover, IL-8 generation was inhibited by PTX,
implying that CysLT2R uses Gi?Go proteins for calcium-
independent signaling in hMCs. Thus, CysLT1R and CysLT2R
have nonredundant functions on hMCs, coupling to distinct
intracellular signaling pathways. Moreover, coexpression of both
Abbreviations: CysLTs, cysteinyl leukotrienes; CysLT2R, type 2 receptor for cysLTs; CysLT1R,
?To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
© 2003 by The National Academy of Sciences of the USA
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CysLTRs may facilitate cooperative recognition of low concen-
in circumstances of inflammation or tissue injury.
Materials and Methods
Calcium Mobilization and Cytokine Generation. hMCs were derived
from cord blood mononuclear cells by culture as described (21).
Cells were harvested when ?95% stained positively with tolu-
idine blue, and were further cultured with either stem cell factor
(SCF, 100 ng?ml, R & D Systems) alone or with SCF and IL-4
(10 ng?ml, R & D Systems) for 5 days at 37°C and 5% CO2.
Changes in the cytostolic free Ca2?concentration elicited by
LTC4and LTD4(both from Cayman Chemical, Ann Arbor, MI)
were measured with fura 2-loaded hMCs (?0.5 ? 106cells per
sample) as described (19).
For cytokine production, IL-4-primed hMCs were stimulated
with LTC4, LTD4, UDP (Sigma), or BAY-u9773 (Biomol, Ply-
mouth Meeting, PA) in triplicate samples of 1 ? 105hMCs in the
wells of 96-well flat bottom plates as described (20). SCF was
included in all stimulation conditions to ensure optimal survival
over the 6-h stimulation period. Supernatants were stored at
?20°C until analysis by commercial ELISA (Endogen, Woburn,
MA). Broad-based cytokine analysis (Perbio, Endogen) was
performed commercially. The cytokine quantities in the samples
corresponding quantities in the samples stimulated with agonists
to obtain the net quantity produced for each cytokine. In some
experiments, hMCs were incubated overnight in the presence of
PTX (100 ng?ml, Sigma), or for 5 min with the selective p38
antagonist SB203580 (10 ?M, Promega) before activation.
MAPK Measurements. MAPK phosphorylation was assessed as
described (20) in response to LTC4and BAY-u9773, both with and
without pretreatment of the cells for 10 min with MK571 (1 ?M,
Cayman Chemical). SDS?PAGE immunoblots were probed with
Abs specific for total ERK, p38, and c-Jun-NH2-terminal kinase
(JNK) MAPKs (Cell Signaling Technologies) and their respective
phosphorylated isoforms (Promega) as described (20).
Measurement of CysLT2R Protein and mRNA Expression. Cytofluoro-
graphic analysis was performed on saponin-permeabilized and
nonpermeabilized hMCs. Samples of 3 ? 105cells were stained
with 2 ?g of polyclonal Abs raised against N-terminal or
C-terminal peptides of the human CysLT2R, or against a C-
terminal peptide from CysLT1R, or with an equivalent amount
of a nonspecific rabbit IgG (all from Cayman Chemical) and
analyzed as described (21). Immunohistochemistry and chloro-
acetate esterase staining was performed on surgically excised
nasal polyps as reported (22). Tissue sections were stained with
1:50 dilutions of the anti-CysLT2 C-terminal peptide Ab, with a
mAb to human ? and ? tryptases (Calbiochem), or with equiv-
alent dilutions of isotype-matched controls. Staining of
CysLT2R was localized to hMCs by using overlaying of images
content, whole hMC lysates were prepared and resolved on
precast SDS?14% polyacrylamide gels (NOVEX, San Diego)
(23). Immunoblots were probed with 1:500 dilutions of anti-
CysLT2R C-terminal Ab, followed by a horseradish peroxidase-
conjugated goat anti-rabbit secondary Ab. Bands were detected
by autoradiography using enhanced chemiluminescence (Amer-
sham Pharmacia). The expression of CysLT1R and CysLT2R
mRNA was assessed by real-time PCR (TaqMan, Applied
Biosystems) as described (24).
Results and Discussion
We first performed a cytofluorographic analysis on cultured
hMCs by using two polyclonal anti-peptide Abs, directed at
permeabilized and nonpermeabilized hMCs were studied to
visualize both intracellular and surface-associated CysLT2R
protein (Fig. 1A). The specificity of the staining was supported
by the fact that the anti-C-terminal Ab raised against an epitope
predicted to reside in the cytosolic tail of the receptor stained
only the permeabilized hMCs. Resident hMCs in two surgically
both Abs (as shown for the C-terminal Ab in one donor, Fig. 2).
Both the pattern of immunohistochemical staining in the polyp
hMCs and the enhanced cytofluorographic staining of perme-
abilized cultured hMCs indicated that a significant portion of
CysLT2R was located intracellularly in hMCs, even in a donor
with very low surface expression at baseline (donor 2, Fig. 1A).
Thus, hMCs express both known CysLTRs, as has been reported
for eosinophils and macrophages (13, 14).
Because IL-4 priming increases the sensitivity of hMCs to
CysLTR-mediated signaling without altering levels of CysLT1R
expression (20), we determined whether this priming event
changed membrane expression of CysLT2R protein. Cytoflu-
orographic analysis of hMCs from 5 consecutive donors revealed
a modest but significant enhancement of CysLT2R membrane
staining in hMCs treated for 5 d with recombinant human IL-4
(10 ng?ml) in the presence of SCF, compared with replicates
maintained in cytoprotective SCF alone (net MFI 43 ? 10 vs.
26 ? 6 arbitrary units, P ? 0.017, mean ? SEM, n ? 5, Fig. 1B).
In four of these five donors, the increase over the baseline
surface expression was caused by the induction of high levels in
a subgroup of hMCs by IL-4 (?10–15% of the total population).
low in the absence of priming, and IL-4 induced an upward shift
in the cytofluorographic peak for CysLT2R in the entire pop-
ulation. IL-4 priming did not substantially alter levels of
CysLT2R staining in permeabilized hMCs using either Ab (as
shown for donor 2 in Fig. 1A), did not change the substantial
intensity of baseline immunodetectable CysLT2R protein on
SDS?PAGE immunoblot (Fig. 1B), and did not change steady-
state levels of CysLT2R mRNA as measured by real-time PCR
(not shown). It is thus likely that the change in surface CysLT2R
largely reflects a redistribution of CysLT2R to the plasma
membrane. In agreement with results reported previously (20),
CysLT1R protein and transcript were also expressed by hMCs,
and neither was altered by IL-4 priming (n ? 3, data not shown).
To determine whether CysLT2R has distinct functions, we
studied ligand-initiated responses in the presence and absence of
the CysLT1R-selective antagonist, MK571. As in our previous
studies (20), IL-4 priming substantially enhanced cysLT-mediated
calcium fluxes of hMCs (data not shown). Nevertheless, MK571 at
1 ?M completely blocked the ability of IL-4-primed hMCs to flux
calcium in response to LTC4(n ? 3, as shown for one experiment
in Fig. 3A) at doses as high as 1 ?M, despite their considerable
expression of CysLT2R. Although it is possible that the capacity of
IL-4 to modestly up-regulate CysLT2R membrane expression on
hMCs is unrelated to its enhancement of cysLT-mediated calcium
flux, it is also possible that CysLT2R cooperates with CysLT1R in
the recognition of cysLTs (LTC4in particular), possibly by forma-
tion of an MK571-sensitive CysLT1R?CysLT2R heterodimer sim-
ilar to those described in other GPCR systems (25).
The absence of a calcium flux in the MK571-treated, LTC4-
stimulated hMCs led us to explore whether CysLT2R, functioning
independently in hMCs, might use signals not dependent on
in robust phosphorylation of ERK. Pretreatment with MK571
(10?6M) completely inhibited ERK phosphorylation (n ? 3, as
shown for 1 donor, Fig. 3B). Thus as with calcium flux, cysLT-
mediated ERK phosphorylation in hMCs requires binding to
CysLT1R. p38 MAPK was phosphorylated even in unstimulated
www.pnas.org?cgi?doi?10.1073?pnas.2034927100Mellor et al.
hMCs and did not differ from the signal obtained from 5 min of
LTC4 stimulation. However, at 30 min, when the signal in the
unstimulated samples was virtually undetectable, LTC4 induced
incremental, MK571-resistant phosphorylation of p38 (n ? 2, as
shown for one donor, Fig. 3B), suggesting that the two known
receptors for cysLTs couple to different MAPK signaling cascades
We next sought differences in secretory functions between the
cysLT-induced generation of IL-5, TNF?, and MIP-1? by 80% or
more, indicating the requirement for CysLT1R (or CysLT1R-like)
receptors for this response (20), while, in retrospect, revealing a
assayed supernatants from IL-4-primed hMCs that had been stim-
of MK571 at a 10-fold molar excess for multiple cytokine and
chemokine products, by using a broad-based ELISA measurement
of multiple cytokine and chemokine products in the same samples
(Perbio System, Endogen). The secretion of most of the cytokines
and chemokines by IL-4-primed, cysLT-stimulated hMCs was
completely or markedly inhibited by MK571 pretreatment. Note-
worthy exceptions included IL-16 and the chemokines monocyte
chemoattractant protein-1 and IL-8.
We focused our further analyses on the CysLT2R-dependent
generation of IL-8 because of the robust nature of this signal, and
contrasted it with the secretion of IL-5 to serve as a control for the
efficacy of the CysLT1R blockade. The blockade of IL-5 secretion
by IL-4-primed hMCs stimulated with LTC4, LTD4, and UDP by a
10-fold molar excess of MK571 contrasted sharply with the com-
10?6M elicited secretion of IL-8 at levels comparable to those
elicited by stimulation with cysLTs or UDP, and also induced IL-5
generation. Pretreatment with PTX or with the p38 inhibitor
SB203580 virtually abolished ligand-induced IL-5 and IL-8 gener-
ation, both with and without MK571 pretreatment (n ? 3, data not
shown). Thus, activation of hMCs through the CysLT2R accounts
for the entirety of cys-LT-dependent IL-8 generation, thereby
establishing the unique effector function of this receptor under
conditions where CysLT1R is blocked. The fact that IL-5 genera-
tion occurs as a result of stimulation with BAY-u9773, but not
cys-LTs under conditions where CysLT1R is blocked, suggests
unique agonistic properties of this compound, possibly by stimu-
lating a CysLT1?CysLT2 heterodimer at a site inaccessible to
interference from MK571. Moreover, the complete inhibition of
CysLT2-dependent IL-8 secretion by PTX implies that CysLT2R
uses Gi?o family proteins to induce secretion in hMCs. This
contrasts with the reported utilization of Gq proteins by the cloned
CysLT2R transfected into Xenopus oocytes (13), and emphasizes
that G protein coupling of a single receptor may differ between cell
types. G proteins of the Gi?o class mediate the function of the
P2Y12 receptor, a homologue of CysLT1R and CysLT2R, without
PLC activation and calcium flux to adenosine diphosphate (26).
CysLT1R (Gq activation, calcium flux, ERK phosphorylation)
an N-terminal epitope. hMCs were treated for 5 days with SCF only (100 ng?ml) or SCF plus IL-4 (10 ng?ml). Histograms are overlayed on tracings elicited
by an IgG control (shaded) and by secondary Ab alone (light tracings). Results from three separate donors (of five tested) are displayed. Intracellular
staining on saponin-permeabilized hMCs with the same anti-N-terminal IgG (N-term), and with an anti-C-terminal IgG (C-term). Results depicted for
intracellular staining are from the cells of donor 2 and are representative of results from four separate donors. (B) Changes in cytofluorographic surface
expression of CysLT2R induced by IL-4 priming, as determined by net MFI. Results are the mean ? SEM of data from five separate experiments. SDS?PAGE
immunoblot (Bottom) from one of these experiments is displayed, depicting the CysLT2R signals for nonprimed and IL-4-primed samples. Results are
representative of three experiments.
Expression of CysLT2R by hMCs. (A) Cytofluorographic surface staining for CysLT2R (bold tracings) by using a rabbit-anti-human IgG directed at
for CysLT2R with the anti-C-terminal Ab (b). (c) The cells were identified as
adjacent sections. (d) Negative control, performed on hMCs in a different
section, is indicated. Results are representative of experiments performed
with polyps from two different patients.
Immunoreactivity for CysLTRs on nasal polyp hMCs. Sections through
Mellor et al.
September 30, 2003 ?
vol. 100 ?
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and CysLT2R (G?i?o activation, p38 phosphorylation). When
CysLT1R is blocked, CysLT2R is still functional and induces a
distinct profile of biochemical events and secreted products, even
though cysLTs cannot induce calcium flux in hMCs under such
circumstances. The fact that IL-5 generation is blocked by MK571
and by inhibitors of downstream signaling for either CysLT1R or
CysLT2R suggests synergy and cooperation of the two receptors
after ligand recognition.
Our study identifies a distinct function for the CysLT2R.
CysLT2R alone accounts for a small MK571-resistant residual
IL-5 generation in response to cysLTs and UDP, and for the
entirety of IL-8 production in response to these ligands (Fig. 4).
IL-8 is a major chemoattractant that may relate to the recruit-
ment of neutrophils to the airways of allergic individuals in
response to experimental allergen challenge, and to the neutro-
phil dominance of bronchial pathology in patients who die
suddenly of status asthmaticus (27). During inflammatory re-
MCs, macrophages, and eosinophils, whereas extracellular nu-
cleotides, including UDP, would be prominent products of
cellular damage and microbial invasion. Each class of ligand
could mediate autocrine and paracrine extracellular signaling in
hematopoietic cells expressing both CysLTRs. Moreover, the
incomplete therapeutic effects of selective CysLT1R antagonists
could reflect their ability to interfere with some, but not all,
effector functions of the CysLTR ligands on hMCs and other
resident tissue cells that express both receptors.
This work was supported by National Institutes of Health Grants
AI-48802, AI-52353, AI-31599, and HL-36110, and by grants from the
Charles Dana Foundation, the Vinik Family Fund for Research in
Allergic Diseases, and the Hyde and Watson Foundation.
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