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*
Core Research for Evolutional Science and Technology, Japan Science and Technology Corp., and
Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in the BAL fluid of TG mice was decreased compared with that in
WT mice. Furthermore, lymphocytes isolated from the lungs of TG mice
secreted less IFN- than those from WT mice, whereas IL-4 production
was unchanged between WT and TG mice. Thus, overproduction of
PGD2 caused an increase in the levels of Th2 cytokines and
a chemokine, accompanied by the enhanced accumulation of eosinophils
and lymphocytes in the lung. These results indicate that
PGD2 plays an important role in late phase allergic
reactions in the pathophysiology of bronchial
asthma. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mast cells, residing in mucosal airways, are believed to orchestrate allergic reactions through the production of various cytokines and lipid mediators after activation by crossing of their high affinity IgE receptors (7). PGD2 is a major cyclo-oxygenase product formed in activated mast cells (8, 9, 10). Indeed, the PGD2 level in bronchoalveolar lavage (BAL)5 fluid increases in response to Ag provocation and, therefore, is used as a marker for activation of mast cells in vivo (11, 12). PGD2 shows a variety of biological actions (13, 14, 15, 16), including vasodilation and bronchoconstriction. Thus, PGD2 is thought to be involved in the acute phase allergic reaction. However, relatively little is known about the role of PGD2 in the late phase reaction of the allergic response, such as eosinophilic lung inflammation in bronchial asthma. In mice with a null mutation of the D-type prostanoid (DP) receptor gene, eosinophil and lymphocyte accumulation in the lungs and the concentration of Th2 cytokines were reduced compared with those in their wild-type (WT) littermates after Ag challenge in a murine asthma model (17), indicating that PGD2 signaling is involved in the regulation of allergic inflammation.
PGD2 is formed from arachidonic acid by
successive enzyme reactions: oxygenation of arachidonic acid to
PGH2, a common precursor of various prostanoids,
catalyzed by cyclo-oxygenase, and isomerization of
PGH2 to PGD2 by PGD
synthase (PGDS). As recently reviewed (18), there are two
distinct types of PGDS: one is the lipocalin-type PGDS (L-PGDS)
(19, 20, 21), and the other is hematopoietic PGDS (H-PGDS)
(22, 23). We isolated the cDNA and the gene for each
enzyme and determined the tissue distribution profile and cellular
localization in several animal species. L-PGDS is localized in the CNS
(24, 25), ocular tissues (26), and male
genital organs (27) of various mammals and the human heart
and is secreted into cerebrospinal fluid (28, 29), seminal
plasma, plasma (30), and urine (31). The
human enzyme was identified as 
-trace, which is a major protein in
human cerebrospinal fluid. This enzyme is considered to be a dual
function protein; it acts as a PGD2-producing
enzyme and also as a lipophilic ligand-binding protein, because the
enzyme binds retinoids, thyroids, and bile pigments with high
affinities. H-PGDS is widely distributed in the peripheral tissues and
is localized in APC, mast cells (22), and megakaryocytes
(32). The hematopoietic enzyme is the first recognized
vertebrate homologue of the sigma class of GST (23). X-ray
crystallographic analyses and generation of gene-knockout and
transgenic (TG) mice for each enzyme have been performed.
In this study we investigated the effect of PGD2 overproduction on the development of late phase allergic inflammation. For this purpose, we used TG mice overexpressing human L-PGDS (33) as an in vivo model of bronchial asthma, because human H-PGDS TG mice showed weaker eosinophilic lung inflammation than L-PGDS TG mice. L-PGDS TG mice showed a pronounced infiltration of eosinophils and lymphocytes and up-regulation of Th2 cytokine production in response to OVA provocation, demonstrating an important role of PGD2 in the development of allergic inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TG mice overexpressing human L-PGDS were generated in the inbred FVB strain as described previously (33). Among five independent founder mice, we used three founders (B7, B17, and B20) in this study. Mice were maintained under specific pathogen-free conditions in isolated cages.
Northern blot analysis
Mice were anesthetized with sodium pentobarbital (Abbott Laboratories, Abbott Park, IL). Lungs were quickly isolated and homogenized in ISOGEN (Nippon Gene, Tokyo, Japan). Total RNA was extracted according to the manufacturer’s instructions, separated (10 µg/lane) on a 1% agarose/2.2 M formaldehyde gel, and transferred to a Biodyne membrane (Pall Ultrafine Filtration, Glen Cove, NY). The blot was hybridized with the 32P-labeled cDNA for human L-PGDS. After being stripped of L-PGDS probe, the blot was hybridized with the 32P-labeled mouse G3PDH cDNA.
Enzyme assay
Lungs were harvested and homogenized in 1 ml ice-cold PBS with a Polytron homogenizer (Brinkmann, Westbury, NY). The homogenates were centrifuged at 100,000 x g at 4°C for 30 min, and the supernatants were used for the enzyme assay, as described previously (20). Protein concentration was determined by use of bicinchoninic acid reagent (Pierce, Rockford, IL) with BSA as a standard following the manufacturer’s protocol.
Western blot analysis
L-PGDS in the lungs of WT and TG mice was partially purified by acid treatment and ammonium sulfate fractionation as reported previously (19). In brief, the 100,000 x g supernatants of the lung homogenates were acidified to pH 4.5 with glacial acetic acid and centrifuged at 10,000 x g for 10 min. The resultant clear supernatant was adjusted to pH 7.0 and fractionated by 55–80% saturated ammonium sulfate. The resultant pellet was dissolved in PBS and subjected to SDS-PAGE. The proteins were transferred to a polyvinylidene difluoride nylon membrane (Millipore, Bedford, MA) and immunostained with polyclonal rabbit anti-human L-PGDS Ab (34) as reported previously (19).
Histologic analysis
Mice were perfused with PBS and subsequently with 4% paraformaldehyde (pH 3.8) through the left ventricle. The lungs were removed and embedded in paraffin. Sections were then cut and stained with H&E. Immunoperoxidase staining was performed as reported previously (35) with rabbit polyclonal Ab against human L-PGDS (34).
Immunization and Ag challenge of mice
TG and WT mice (females, 25–30 g, 14–16 wk old) were immunized
i.p. with 10 µg OVA (grade V, Sigma, St. Louis, MO) in 0.2 ml alum
(Serva, Heidelberg, Germany) on days 0 and 14. On day 21 the mice were
exposed to aerosolized OVA (50 mg/ml sterile saline) for 20 min. At
specified times after the OVA challenge the mice were anesthetized with
sodium pentobarbital. The trachea was cannulated, and BAL was performed
by three repeated lavages with 0.3 ml saline injected into the lungs
via the tracheal cannula. Total cells were counted, and differential
cell counts with 500 cells were performed based on standard morphologic
criteria. For determination of the amounts of Th2 cytokines, eotaxin,
and total IgE, BAL fluid and serum were collected 24 h after OVA
provocation. The levels of IL-4, IL-5, eotaxin, and IFN- were
determined with the respective ELISA kits (BioSource, Camarillo, CA).
Total IgE titers were determined with an ELISA kit (Yamasa, Chiba,
Japan). OVA-specific IgE was quantified by incubation of mouse serum in
ELISA plates precoated with monoclonal anti-mouse IgE followed by
incubation with biotinylated OVA (BD PharMingen, San Diego, CA) and
alkaliphosphatase-conjugated streptavidin (BD PharMingen).
Measurement of PGs in the lung
The amounts of PGD2 and PGE2 in the lungs were determined as described previously (33). Briefly, the lungs were homogenized in 2 ml ethanol containing 0.25 N HCl with a Polytron homogenizer. [3H]PGD2 and PGE2 (NEN Life Science Products, Boston, MA) were added to each homogenate as tracers to determine the recovery during the purification procedure. PGs in the ethanol extract were applied onto Sep-Pak C18 cartridges (Waters Associates, Milford, MA), eluted with ethyl acetate, and then fractionated by HPLC. The amounts of PGs were measured with the respective kits (Cayman Chemical, Ann Arbor, MI).
Quantitative RT-PCR of mRNAs for DP and CRTH2 receptors in the lung
First-strand cDNA was transcribed from 1 µg total RNA obtained from the lung, with random primers by AMV reverse transcriptase (Takara Shuzo, Kyoto, Japan). For quantitative PCR, we amplified DNA using a LightCycler (Roche, Mannheim, Germany), a LightCycler-DNA Master SYBR Green I Kit (Roche), and primers specific for mouse G3PDH, (5'-TGAACGGGAAGCTCACTGG-3' and 5'-TACAGCAACAGGGTGGTGGA-3'), mouse DP receptors (5'-TTTGGGAAGTTCGTGCAGTACT-3' and 5'-GCCATGAGGCTGGAGTAGA-3') (36), and mouse CRTH2 receptors (5'-TGGCCTTCTTCAACAGCGT-3' and 5'-ACGCAGTTGGGGAATTCG-3') (37). The reactions were cycled 40 times with denaturation at 95°C for 3 s, annealing for G3PDH and DP receptors at 57°C, annealing for CRTH2 receptors at 58°C for 5 s, and elongation at 72°C for 10 s. Temperature gradients for denaturation, annealing, and elongation were 20, 2, and 20°C/s, respectively. Fluorescence was acquired after heating at 20°C/s to a temperature of 2°C below the product melting temperature and maintaining this temperature for 1 s. Quantification data were analyzed with LightCycler analysis software. All PCR products were sequenced to confirm their origin from the intended mRNAs.
In vitro T cell cytokine secretion
The lungs were perfused via the right ventricle with 5 ml PBS
containing 100 U/ml heparin to remove any blood and intravascular
leukocytes. The lungs were then removed and placed into DMEM containing
10% FCS, 2-ME (50 µM), L-glutamine (2 mM), sodium
pyruvate (1 mM), HEPES (10 mM), and gentamicin (50 µg/ml). They were
then gently homogenized, the cell suspension was filtered through a
70-µm pore size filter, and the lymphocyte population was enriched by
centrifugation on a single-step Ficoll gradient. The lymphocyte
fraction was plated at a concentration of 2 x
105 cells in 96-well plates coated with
anti-CD3 Ab (50 µg/ml; BD PharMingen). The cells were
cultured for 3 days in the presence of human IL-2 (200 U/ml; BD
PharMingen). The supernatants were harvested, and cytokine production
(IL-4 and IFN-) was determined by ELISA.
Statistical analysis
The results of the experiments were expressed as the mean ± SEM. Student’s t test was used for the statistical analysis in cases in which the variance was homogeneous, and Welch’s test was used when the variance was heterogeneous. A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As previously reported we had established five independent
founders of TG mice (33). Based on the level of transgene
expression, we chose three lines of TG mice (B7, B17, and B20) for this
study. As shown in Fig. 1
A,
human L-PGDS mRNA was expressed in the lungs of all three lines of TG
mice. The L-PGDS-immunoreactive protein was also detected to be
overexpressed in the lungs of TG mice (Fig. 1B). To confirm
that the expressed transgene is functional in the lung, we measured
PGDS activity in lung homogenates with PGH2 as a
substrate. As shown in Fig. 1C, PGDS activities in the lung
homogenates from the three lines of TG mice, i.e., B7, B17, and B20,
were 3.2-, 2.0-, and 3.6-fold higher, respectively, than that from WT
mice. These results indicate the functional expression of the transgene
in the lungs of these mice. The transgene was expressed in airway
epithelium, sub-bronchial and ventricular smooth muscle cells, and
alveolar lining cells of three lines of TG mice, as examined by
immunostaining with anti-human L-PGDS Ab. Typical results obtained
with B20 mice are shown in Fig. 1, D and E.
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These TG mice were then used in an OVA-induced lung inflammation
model. No eosinophils, neutrophils, or lymphocytes were observed in the
BAL fluid of either WT or TG mice before and after saline challenge.
The numbers of alveolar macrophages before and after saline challenge
were not significantly different among WT, B7, B17, and B20 mice
(4.2 ± 0.7 and 5.2 ± 0.6, 6.8 ± 1.8 and 4.9 ±
0.5, 3.7 ± 1.9 and 4.7 ± 0.6, and 8.5 ± 2.0 and
4.3 ± 0.4 x 104 cells/ml,
respectively; n = 6–7). BAL fluid was collected on
days 1 and 3 after OVA challenge. One day after OVA challenge the
numbers of macrophages in BAL fluid were almost the same as that in the
saline-challenged group (Fig. 2). The
number of macrophages in BAL fluid was increased in both WT and TG mice
on day 3 postchallenge without any significant difference between WT
and TG mice. Infiltration of neutrophils into the lungs was observed on
day 1 postchallenge and was resolved on day 3, but the cell numbers
were unchanged between WT and TG mice. However, infiltration of
eosinophils in B17 and B20 mice was increased by 4.0- and 3.9-fold
(12.9 ± 2.9 and 12.5 ± 2.5 x
104 cells/ml) on day 1 and by 2.2- and 1.6-fold
(31.8 ± 4.9 and 22.8 ± 3.9 x
104 cells/ml) on day 3, respectively, compared
with that in WT mice (3.2 ± 1.7 and 14.2 ± 2.7 x
104 cells/ml on days 1 and 3, respectively). B7
mice also appeared to show higher eosinophilia (7.2 ± 2.4 and
16.3 ± 3.0 x 104 cells/ml on days 1
and 3, respectively) than WT mice, although the difference was not
statistically significant. Furthermore, the number of lymphocytes was
increased in all three lines of TG mice by 7.4-, 5.7-, and 6.8-fold
(0.56 ± 0.1, 0.43 ± 0.05, and 0.52 ± 0.11 x
104 cells/ml; B7, B17, and B20 mice,
respectively) compared with that in WT mice (0.08 ± 0.05 x
104 cells/ml) on day 1. Three days post OVA
challenge, B17 and B20 mice showed a significant increase in
lymphocytes compared with WT mice.
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Eosinophils infiltrated into the peribronchial region of B17 mice more
significantly than in WT mice.
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PGD2 content is increased in the lung during the late phase allergic reaction in TG mice
The PGD2 content in the lungs of WT and TG
mice was determined before and after OVA challenge. As shown in Fig. 4, the PGD2 content
in the lungs of the unchallenged WT and B17 mice was low and
statistically unchanged (0.51 ± 0.01 and 0.72 ± 0.40
ng/lung, WT and B17 mice, respectively). However, the
PGD2 content significantly increased 30 min after
OVA challenge in both WT and TG mice (1.47 ± 0.18 and 1.26
± 0.06 ng/lung, respectively), although no significant difference was
observed between WT and TG mice. The production of
PGD2 at 30 min may be attributed to mast cells
and macrophages that express endogenous H-PGDS. Accumulation of the
other inflammatory cells, including eosinophils and neutrophils, began
approximately 3 h after challenge, and these cells expressing
L-PGDS in the TG mice contributed to the higher production of
PGD2 assessed 6 h after challenge. The
PGD2 content reached its peak at 6 h
post-OVA challenge, at which time point the content in TG mice
(4.38 ± 0.88 ng/lung) was 2.3-fold higher than that in WT mice
(1.94 ± 0.88 ng/lung). Furthermore, 24 h after OVA
challenge, the content remained significantly higher in TG mice
(3.0 ± 0.34 ng/lung) than in WT mice (1.11 ± 0.50 ng/lung).
In contrast to PGD2, the level of
PGE2, another inflammatory prostanoid, in the
lungs was the same before and after OVA challenge in either group.
These results indicate that the human L-PGDS overexpressed in the lungs
of TG mice functioned to overproduce PGD2 in
response to the OVA challenge without affecting
PGE2 biosynthesis.
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We then examined the possible changes in the expression level of
PGD2 receptors by the overproduction of
PGD2. There are two distinct types of
PGD2 receptors, i.e.,
Gs-coupled DP receptors (36, 38) and
Gi-coupled CRTH2 receptors (39, 40).
We determined by RT-PCR the contents of mRNAs for DP and CRTH2
receptors in the lungs of WT and TG mice before and after OVA
challenge. As shown in Fig. 5, the mRNA
for DP receptors was increased 2- to 3-fold in the lungs of WT and TG
mice 2 days after OVA challenge. However, the DP mRNA content was
statistically unchanged between WT and TG mice either 1 or 2 days after
OVA challenge. On the other hand, the content of mRNA for CRTH2
receptors in the lungs of WT and TG mice before OVA challenge was
100-fold or higher than that of mRNA for DP receptors. The CRTH2 mRNA
content was almost unchanged or was slightly decreased in both mice
after OVA challenge.
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Given the important role of Th2 cytokines and chemokines in
allergic inflammation, we determined the levels of IL-4, IL-5, IFN-,
and eotaxin in the BAL fluid of WT and TG mice after OVA provocation.
Low levels of IL-4 and IL-5 (<10 pg/ml) were detected in the BAL fluid
of WT and TG mice after saline challenge (Fig. 6A). After OVA provocation,
however, Th2 cytokine levels were increased in both WT and TG mice.
IL-4 and IL-5 in BAL fluid of the challenged TG mice (IL-4, 298.9
± 119.6 pg/ml; IL-5, 358.7 ± 48.9 pg/ml) were 3.9- and 2.4-fold,
respectively, higher than those in WT mice (IL-4, 77.2 ± 27.2
pg/ml; IL-5, 152.2 ± 54.4 pg/ml). Furthermore, the eotaxin level
in TG mice (36.5 ± 1.7 pg/ml) was significantly higher than that
in WT mice (22.1 ± 1.2 pg/ml) after OVA challenge. In contrast to
Th2 cytokines and eotaxin, IFN- content in BAL fluid of TG mice
(10.0 ± 1.6 pg/ml) was significantly decreased compared with that
in WT mice (21.0 ± 1.7 pg/ml). To determine the extent of
systemic immune modulation by OVA challenge, we determined serum levels
of IL-5, total IgE, and OVA-specific IgE (Fig. 6B). Although
serum IL-5 levels in WT and TG mice increased after OVA challenge,
there was no significant difference between the two groups of mice.
Furthermore, the total IgE level and the OVA-specific IgE level in the
serum were the same in WT and TG mice after either saline or OVA
challenge.
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Since Th2 cytokine levels were increased in the BAL fluid of TG
mice, we isolated lung lymphocytes and stimulated them with
anti-CD3 Ab to examine their cytokine secretion patterns. As shown
in Fig. 7, lung lymphocytes from both WT
and TG mice challenged with OVA produced both IL-4 and IFN-.
Although there was no significant difference in IL-4 secretion between
WT and TG mice (312.0 ± 35.0 and 259.0 ± 27.0 pg/ml,
respectively), IFN- secretion from TG mice (4.2 ± 0.6 pg/ml)
was significantly lower than that from WT mice (11.8 ± 0.6
pg/ml), suggesting that lymphocytes in lungs from TG mice showed a
Th2-declined phenotype.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The levels of CC chemokines, such as eotaxin, RANTES, monocyte
chemoattractant protein-3, and monocyte chemoattractant protein-4,
which are selective chemoattractants for eosinophils (44),
are increased in BAL fluid and lungs in response to Ag provocation
(45, 46). In asthmatics, Th2 lymphocytes are increased in
number in the airways after an Ag challenge (47, 48). Th2
cells produce IL-4 and IL-5, both cytokines contribute to the
development of IgE-producing B cells, and IL-5 supports the
proliferation of eosinophils. We show that PGD2
overproduction increased IL-4, IL-5, and eotaxin and down-regulated
IFN- in BAL fluid of TG mice (Fig. 6
), suggesting that
PGD2 produces a decrease in Th2 in the lung
microenvironment after Ag provocation. Indeed, lung lymphocytes,
isolated from TG mice, showed a decreased Th2 cytokine production
pattern in vitro; its IFN- secretion was specifically decreased
compared with that in WT mice (Fig. 7).
Most recently, PGD2 was identified as a ligand for a Gi protein-coupled, seven-transmembrane-type receptor, CRTH2 (39), which is preferentially expressed in Th2 cells, eosinophils, and basophils, and PGD2 was shown to induce chemotaxis of these cells through CRTH2, but not through DP receptors (40). Thus, the direct chemoattractant action of PGD2 on CRTH2-possessing cells may explain the pronounced infiltration of eosinophils and lymphocytes and the increased Th2 cytokines in the BAL fluid of L-PGDS TG mice upon OVA challenge. Furthermore, these observations address the possibility that PGD2 functions as an allergic mediator through both CRTH2 and DP receptors and, more importantly, highlight the role of the PGD2 biosynthesis pathway in allergic lung inflammation.
In asthmatic airways, cyclo-oxygenase-2, an inducible isoform of cyclo-oxygenase, is up-regulated (49, 50), suggesting the possible involvement of cyclo-oxygenase products, including PGD2, in the pathogenesis of this disease. In an experimental animal model of bronchial asthma, nonsteroidal anti-inflammatory drugs, such as indomethacin and aspirin, were found to have a negative impact on Ag-induced eosinophilic lung inflammation (51). However, the inhibition of cyclo-oxygenase by nonsteroidal anti-inflammatory drugs abrogates the production of all PGs. Especially PGE2 and prostacyclin are bronchodilatory PGs with an anti-inflammatory effect (52). Thus it is necessary to use specific inhibitors of PGD2 receptors or PGDS to determine the role of PGD2 in this model.
It is well known that mast cells express H-PGDS and secrete PGD2 in response to Ag stimulation (8). It was also reported that Th2 cells, but not Th1 cells, express H-PGDS and produce PGD2 after TCR activation (53). Thus, it is very likely that both mast cells and Th2 cells, which infiltrate into the allergic inflammatory site, produce PGD2 upon Ag stimulation to regulate the allergic conditions. Recently, it was reported that HQL-79, an inhibitor of H-PGDS, efficiently inhibited Ag-induced eosinophilic lung inflammation in guinea pigs (54, 55). Thus, H-PGDS will be a target for drugs designed for bronchial asthma and other allergic diseases.
The cysteinyl leukotrienes have been implicated in the pathophysiology of bronchial asthma. They elicit contraction of bronchial smooth muscle cells and vascular smooth muscle cells. The latter induces extravasation of plasma protein and accumulation of inflammatory cells such as Th2 cells and eosinophils. Activation of constitutive mast cells residing in the lung to release PGD2 would cause accumulation of Th2 cells and eosinophils via CRTH2 with generation of polarized cytokines, which, in turn, expand phenotypically distinct mucosal mast cells (reactive mast cells) shifted to the cysteinyl leukotriene pathway (56). PGD2 also elicits relaxation of smooth muscle cells and endothelial cells via DP and may induce lung inflammation, as proposed in the study of DP receptor knockout mice (17). These inflammatory cells, including reactive mast cells, further generate PGD2, contributing to a positive feedback of the allergic and asthmatic inflammation where a range of cytokines and chemokines are produced so as to sustain the Th2-dependent inflammatory allergic and asthmatic responses.
In summary, we used TG mice overexpressing human L-PGDS to examine the effect of overproduction of PGD2 on the development of allergic inflammation with a murine asthma model. We show that overproduction of PGD2 caused an increase in the levels of Th2 cytokines and a chemokine accompanied by the enhanced accumulation of eosinophils and lymphocytes in the lung. These results indicate that PGD2 plays an important role in late phase allergic reactions in the pathophysiology of bronchial asthma.
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Acknowledgments |
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Footnotes |
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2 Current address: Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Osaka 532-8686, Japan. E-mail address: Fujitani_Yasushi{at}takeda.co.jp
3 Current address: Department of Medicine, Harvard Medical School, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA 02115.
4 Address correspondence and reprint requests to Dr. Yoshihiro Urade, Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. E-mail address: uradey{at}obi.or.jp
5 Abbreviations used in this paper: BAL, bronchoalveolar lavage; TG, transgenic; H-PGDS, hematopoietic PGD synthase; DP, D-type prostanoid; L-PGDS, lipocalin-type PGD synthase; PGDS, PGD synthase; WT, wild type.
Received for publication February 13, 2001. Accepted for publication October 25, 2001.
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M. Joo, M. Kwon, R. T. Sadikot, P. J. Kingsley, L. J. Marnett, T. S. Blackwell, R. S. Peebles Jr, Y. Urade, and J. W. Christman Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity J. Immunol., August 15, 2007; 179(4): 2565 - 2575. [Abstract] [Full Text] [PDF]
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M. Joo, J. G. Wright, N. N. Hu, R. T. Sadikot, G. Y. Park, T. S. Blackwell, and J. W. Christman Yin Yang 1 enhances cyclooxygenase-2 gene expression in macrophages Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1219 - L1226. [Abstract] [Full Text] [PDF]
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 H. Hammad, M. Kool, T. Soullie, S. Narumiya, F. Trottein, H. C. Hoogsteden, and B. N. Lambrecht Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells J. Exp. Med., February 19, 2007; 204(2): 357 - 367. [Abstract] [Full Text] [PDF]
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 H. Sandig, J. E. Pease, and I. Sabroe Contrary prostaglandins: the opposing roles of PGD2 and its metabolites in leukocyte function J. Leukoc. Biol., February 1, 2007; 81(2): 372 - 382. [Abstract] [Full Text] [PDF]
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W. M. Gwinn, J. M. Damsker, R. Falahati, I. Okwumabua, A. Kelly-Welch, A. D. Keegan, C. Vanpouille, J. J. Lee, L. A. Dent, D. Leitenberg, et al. Novel Approach to Inhibit Asthma-Mediated Lung Inflammation Using Anti-CD147 Intervention J. Immunol., October 1, 2006; 177(7): 4870 - 4879. [Abstract] [Full Text] [PDF]
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T. Satoh, R. Moroi, K. Aritake, Y. Urade, Y. Kanai, K. Sumi, H. Yokozeki, H. Hirai, K. Nagata, T. Hara, et al. Prostaglandin D2 Plays an Essential Role in Chronic Allergic Inflammation of the Skin via CRTH2 Receptor J. Immunol., August 15, 2006; 177(4): 2621 - 2629. [Abstract] [Full Text] [PDF]
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G. Y. Park and J. W. Christman Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L797 - L805. [Abstract] [Full Text] [PDF]
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 H. E. Killer, G. P. Jaggi, J. Flammer, N. R. Miller, and A. R. Huber The optic nerve: a new window into cerebrospinal fluid composition? Brain, April 1, 2006; 129(4): 1027 - 1030. [Abstract] [Full Text] [PDF]
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F. P. Mesquita-Santos, A. Vieira-de-Abreu, A. S. Calheiros, I. H. Figueiredo, H. C. Castro-Faria-Neto, P. F. Weller, P. T. Bozza, B. L. Diaz, and C. Bandeira-Melo Cutting Edge: Prostaglandin D2 Enhances Leukotriene C4 Synthesis by Eosinophils during Allergic Inflammation: Synergistic In Vivo Role of Endogenous Eotaxin J. Immunol., February 1, 2006; 176(3): 1326 - 1330. [Abstract] [Full Text] [PDF]
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R. S. Peebles Jr, K. Hashimoto, J. R. Sheller, M. L. Moore, J. D. Morrow, S. Ji, J. A. Elias, K. Goleniewska, J. O'Neal, D. B. Mitchell, et al. Allergen-Induced Airway Hyperresponsiveness Mediated by Cyclooxygenase Inhibition Is Not Dependent on 5-Lipoxygenase or IL-5, but Is IL-13 Dependent J. Immunol., December 15, 2005; 175(12): 8253 - 8259. [Abstract] [Full Text] [PDF]
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L. Xue, S. L. Gyles, F. R. Wettey, L. Gazi, E. Townsend, M. G. Hunter, and R. Pettipher Prostaglandin D2 Causes Preferential Induction of Proinflammatory Th2 Cytokine Production through an Action on Chemoattractant Receptor-Like Molecule Expressed on Th2 Cells J. Immunol., November 15, 2005; 175(10): 6531 - 6536. [Abstract] [Full Text] [PDF]
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A. N. Hata, T. P. Lybrand, and R. M. Breyer Identification of Determinants of Ligand Binding Affinity and Selectivity in the Prostaglandin D2 Receptor CRTH2 J. Biol. Chem., September 16, 2005; 280(37): 32442 - 32451. [Abstract] [Full Text] [PDF]
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E. Chevalier, J. Stock, T. Fisher, M. Dupont, M. Fric, H. Fargeau, M. Leport, S. Soler, S. Fabien, M.-P. Pruniaux, et al. Cutting Edge: Chemoattractant Receptor-Homologous Molecule Expressed on TH2 Cells Plays a Restricting Role on IL-5 Production and Eosinophil Recruitment J. Immunol., August 15, 2005; 175(4): 2056 - 2060. [Abstract] [Full Text] [PDF]
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K. Fujimori, K. Kadoyama, and Y. Urade Protein Kinase C Activates Human Lipocalin-type Prostaglandin D Synthase Gene Expression through De-repression of Notch-HES Signaling and Enhancement of AP-2{beta} Function in Brain-derived TE671 Cells J. Biol. Chem., May 6, 2005; 280(18): 18452 - 18461. [Abstract] [Full Text] [PDF]
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 W. Almishri, C. Cossette, J. Rokach, J. G. Martin, Q. Hamid, and W. S. Powell Effects of Prostaglandin D2, 15-Deoxy-{Delta}12,14-prostaglandin J2, and Selective DP1 and DP2 Receptor Agonists on Pulmonary Infiltration of Eosinophils in Brown Norway Rats J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 64 - 69. [Abstract] [Full Text] [PDF]
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I. Spik, C. Brenuchon, V. Angeli, D. Staumont, S. Fleury, M. Capron, F. Trottein, and D. Dombrowicz Activation of the Prostaglandin D2 Receptor DP2/CRTH2 Increases Allergic Inflammation in Mouse J. Immunol., March 15, 2005; 174(6): 3703 - 3708. [Abstract] [Full Text] [PDF]
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Y. Shiraishi, K. Asano, T. Nakajima, T. Oguma, Y. Suzuki, T. Shiomi, K. Sayama, K. Niimi, M. Wakaki, J. Kagyo, et al. Prostaglandin D2-Induced Eosinophilic Airway Inflammation Is Mediated by CRTH2 Receptor J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 954 - 960. [Abstract] [Full Text] [PDF]
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G. Monneret, R. Boumiza, S. Gravel, C. Cossette, J. Bienvenu, J. Rokach, and W. S. Powell Effects of Prostaglandin D2 and 5-Lipoxygenase Products on the Expression of CD203c and CD11b by Basophils J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 627 - 634. [Abstract] [Full Text] [PDF]
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A. K. Mandal, Z. Zhang, R. Ray, M. S. Choi, B. Chowdhury, N. Pattabiraman, and A. B. Mukherjee Uteroglobin Represses Allergen-induced Inflammatory Response by Blocking PGD2 Receptor-mediated Functions J. Exp. Med., May 17, 2004; 199(10): 1317 - 1330. [Abstract] [Full Text] [PDF]
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 T. Inoue, Y. Okano, Y. Kado, K. Aritake, D. Irikura, N. Uodome, N. Okazaki, S. Kinugasa, H. Shishitani, H. Matsumura, et al. First Determination of the Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase J. Biochem., March 1, 2004; 135(3): 279 - 283. [Abstract] [Full Text] [PDF]
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E. Bohm, G. J. Sturm, I. Weiglhofer, H. Sandig, M. Shichijo, A. McNamee, J. E. Pease, M. Kollroser, B. A. Peskar, and A. Heinemann 11-Dehydro-thromboxane B2, a Stable Thromboxane Metabolite, Is a Full Agonist of Chemoattractant Receptor-homologous Molecule Expressed on TH2 Cells (CRTH2) in Human Eosinophils and Basophils J. Biol. Chem., February 27, 2004; 279(9): 7663 - 7670. [Abstract] [Full Text] [PDF]
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M. Shichijo, H. Sugimoto, K. Nagao, H. Inbe, J. A. Encinas, K. Takeshita, K. B. Bacon, and F. Gantner Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells Activation in Vivo Increases Blood Leukocyte Counts and Its Blockade Abrogates 13,14-Dihydro-15-keto-prostaglandin D2-Induced Eosinophilia in Rats J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 518 - 525. [Abstract] [Full Text] [PDF]
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K. Honda, M. Arima, G. Cheng, S. Taki, H. Hirata, F. Eda, F. Fukushima, B. Yamaguchi, M. Hatano, T. Tokuhisa, et al. Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine J. Exp. Med., August 18, 2003; 198(4): 533 - 543. [Abstract] [Full Text] [PDF]
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A. N. Hata, R. Zent, M. D. Breyer, and R. M. Breyer Expression and Molecular Pharmacology of the Mouse CRTH2 Receptor J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 463 - 470. [Abstract] [Full Text] [PDF]
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 M. A. Carey, D. R. Germolec, J. A. Bradbury, R. A. Gooch, M. P. Moorman, G. P. Flake, R. Langenbach, and D. C. Zeldin Accentuated T Helper Type 2 Airway Response after Allergen Challenge in Cyclooxygenase-1-/- but Not Cyclooxygenase-2-/- Mice Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1509 - 1515. [Abstract] [Full Text] [PDF]
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A. Heinemann, R. Schuligoi, I. Sabroe, A. Hartnell, and B. A. Peskar {Delta}12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis J. Immunol., May 1, 2003; 170(9): 4752 - 4758. [Abstract] [Full Text] [PDF]
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R. Pedotti, J. J. DeVoss, S. Youssef, D. Mitchell, J. Wedemeyer, R. Madanat, H. Garren, P. Fontoura, M. Tsai, S. J. Galli, et al. Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination PNAS, February 18, 2003; 100(4): 1867 - 1872. [Abstract] [Full Text] [PDF]
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G. Monneret, C. Cossette, S. Gravel, J. Rokach, and W. S. Powell 15R-Methyl-Prostaglandin D2 Is a Potent and Selective CRTH2/DP2 Receptor Agonist in Human Eosinophils J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 349 - 355. [Abstract] [Full Text] [PDF]
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