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Unité 547, Institut National de la Santé et de la Recherche Médicale, Institut Fédératif de Recherche 17, Institut Pasteur de Lille, Lille, France
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Mast cells indirectly participate in asthmatic reactions (1). IgE-dependent mast cell activation exacerbates development of airway hyperresponsiveness (AHR) (2). Presence of mast cells also potentiates AD (3). Upon activation by IgE and multivalent Ag, mast cells release several inflammatory mediators such as histamine, proteases, cytokines, and eicosanoids, including leukotrienes and PGs. Among the later, PGD2 is the most abundantly produced. During acute asthmatic episodes, PGD2 is released by mast cells into the lungs (4) and causes bronchoconstriction (5). PGD2, as well as histamine, directly activates eosinophils (6), promotes their recruitment (7), and affects other key parameters of lung inflammation, in particular vascular permeability (1). The role of PGD2 in eosinophilia and lung allergic response has been recently demonstrated using transgenic (Tg) mice that overexpress PGD2 synthase (8). Furthermore, PGD2 nebulization before aerosol Ag challenge enhances Th2-type inflammatory responses, including eosinophilia, and leads to the development of AHR by increasing bronchial expression of macrophage-derived chemokines (9).
PGD2 directly acts through the D prostanoid receptor (DP)1 (G
s coupled) and DP2 (also known as chemoattractant receptor-homologous molecule expressed on Th2 cells or CRTH2) (GI coupled), two membrane-bound receptors that exert broadly antagonistic effects. Within the immune system, DP1 activation affects the maturation process and the migratory ability of human and mouse dendritic cells (DC), a key cell population involved in the initiation and the regulation of the immune response (10, 11, 12). On the other hand, DP2 was identified in humans on type 2 polarized lymphocytes (Th2 and Tc2) (13), basophils, eosinophils (14), and monocytes (12). Previous studies have revealed that DP2 mediates eosinophil chemotaxis induced by mast cell products (14) and was later identified as a PGD2 receptor (15). DP2 activation thus accounts for the PGD2-induced eosinophil chemotaxis and degranulation, whereas DP1 activation delays their apoptosis onset (16). Finally, the number of DP2+ cutaneous lymphocyte Ag+ lymphocytes is increased in patients with AD (17), whereas DP1 activation decreased inflammation in a murine model of AD (18).
Most of the studies on DP2 have been undertaken on human eosinophils in vitro. Data on DP2 in mice are scarce. Mouse DP2 shares a 77% homology with its human counterpart (19) and is activated by PGD2, 13,14-dihydro-15-keto-PGD2 (DK-PGD2), 15-deoxy-
12,14-PGJ2, and indomethacin (20). However, DP2 is not preferentially expressed on Th2-type cells, as it is in humans, and is found on both Th1 and Th2 clones (19 and our unpublished observations). DP2 function might thus be different in mice and humans. Since no data are available so far on DP2 functions in vivo, the use of animal models is required to delineate its role in both physiology and pathology. We thus investigated DP2 involvement in allergic pathologies, in particular in eosinophilia, using two mouse models of allergic inflammation, faithfully mimicking the corresponding human diseases: asthma and AD. In these models, we show that DP2 activation exacerbates pathology.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Female BALB/cJ mice (6–8 wk old) were purchased from Charles River and kept at the Institut Pasteur de Lille under specific pathogen-free conditions. Tg mice expressing IL-5 under the control of human CD2 promoter (21) were used for eosinophil purification. Experiments were performed according to local ethical guidelines.
Cell preparation
Eosinophils were purified from IL-5 Tg mouse spleen by negative selection, as described (22), using anti-CD8, anti-CD90, and anti-B220 Abs (BD Pharmingen). Purity was >90%.
RNA isolation and RT-PCR
Total RNA was isolated using RNAplus (Qbiogene). Reverse transcription was performed with 1 µg of RNA using SuperScript RT. Mouse DP1- and DP2-specific fragments and 
-actin were amplified using the following primers and conditions. DP1, 5'-GAAGTTCGTGCAGTACTGTCCAG-3' (sense); 5'-TCCACTATGGAAATCACAGAC-3' (antisense). DP2, 5'-CATGTGCTACTACAACTTGC-3' (sense); 5'-GCAGACTGAAGATGTGGTAGG-3' (antisense). -Actin, 5'-TCACCGAGGCCCCCCTGAAC-3' (sense); 5'-GCACGCACTGTAATTCCTC-3' (antisense). Annealing temperature was 54, 55, and 60°C for DP1, DP2, and -actin, respectively. Amplification was performed for 40 cycles for DP1 and DP2 and for 25 cycles for -actin. Amplicon size was 435, 262, and 324 bp for DP1, DP2, and -actin, respectively. To exclude potential amplification from contaminating genomic DNA, control experiments, where the reverse transcription step was omitted, were performed. Gel loadings of amplified products were normalized according to the signal from -actin. KmDP53 and KmB20 cells (K562 cells, respectively, transfected by mouse DP1 and DP2 cDNA) were kindly provided by Prof. K. Sugamura (Tohoku University, Japan).
Chemotaxis assay
Eosinophil chemotaxis assay was performed in Boyden chambers as described (23). BW245C and DK-PGD2 (Cayman Chemical) as well as CCL11 (Preprotech) were used as chemoattractants. Except for CCL11, stock solutions (10–2 M) were prepared in DMSO (Sigma-Aldrich). Cells that had migrated and adhered to filter were counted from four fields for each experimental condition.
Ag-induced AHR
Mice were sensitized by i.p. injection with 50 µg of OVA in 100 µl of alum (Imject; Pierce) or received alum only and were challenged for 20 min, on days 14, 16, 18, 20, and 22 by aerosol nebulization with OVA (1% in PBS) using an ultrasonic nebulizer (Systam). Groups of unsensitized or sensitized animals were additionally nebulized with 50 µM DK-PGD2 or BW245C (stock 10–2 M in ethanol) in PBS for 20 min immediately before and during each OVA challenge (23), whereas the corresponding untreated groups were nebulized with an equivalent amount of ethanol. Serum was collected on day 23, and AHR to increasing concentrations of methacholine was measured by whole body plethysmography (Emka) on day 24. Results were expressed as Penh values (24). Lungs were used either for bronchoalveolar lavages (BAL) or for histological analyses and determination of cytokine content in protein extracts. Cytokine content was determined in lung protein extracts (250 µl per right lung) prepared as described (23) using specific ELISA (R&D Systems) for IL-5. BAL were analyzed on cytospin preparations following RAL 555 staining.
Atopic dermatitis
AD was induced by epicutaneous sensitization with OVA as described (25). Two paper disc inserts of a Finn Chamber (Promedica) were applied on abdominal skin 24 h after shaving after soaking with 25 µl of OVA solution (2 mg/ml in PBS) or with PBS. Patches were secured to the skin with a bioocclusive dressing (Visulin; Hartmann), itself protected with an elastic bandage (Optiplaste; Smith & Nephew). Patches were left on for three 1-wk periods (with patch renewal at mid-week) with a 2-wk interval between application. Immediately before patch application, abdomens were topically treated with 25 µl of 50 µM DK-PGD2 (stock 10–2 M in DMSO) in acetone/olive oil (4:1 v/v), whereas the corresponding untreated mice were receiving an equivalent volume of DMSO. Blood was collected on day 49, at the time of last patch removal, and animals were sacrificed on the next day by cervical dislocation. Skin samples were collected for histological analyses.
Histology
Samples were fixed in ImmunoHistoFix (Intertiles) for 7 days at 4°C, then included in ImmunoHistoWax (Intertiles) after ethanol dehydration. Serial 5-µm transversal sections were prepared, dewaxed in acetone, and stained with May-Grunwald-Giemsa (MGG) for general histology and eosinophil counts and with acidic toluidine blue for mast cell counts. For each skin section, 10 random fields were examined at 1000-fold magnification. The various cell types in dermis were enumerated using an eyepiece equipped with a calibrated grid. Results were expressed as cell number per square millimeter. Epidermal thickness was determined at 200-fold magnification with an ocular micrometer. The average of 10 measures was calculated for each sample. For lung sections, the number of eosinophils was determined by counting the total number of eosinophil present in a whole lung section and by measuring the total surface of the lung section (three non-serial sections were used for each sample). Results were expressed as cell number per square millimeter.
Measurement of Ig concentrations
Serum anti-OVA IgG1 were measured by ELISA, using OVA-coated plates and HRP-conjugated anti-mouse IgG1 (Southern Biotechnologies) (23). Serum anti-OVA IgE was measured by ELISA using anti-IgE (BD Pharmingen) as previously described (23). Biotinylated Ab and biotinylated OVA and HRP-conjugated streptavidin (Amersham Biosciences) were used for detection. Serial dilutions (2-fold) were prepared (starting dilution 1/25 for IgE and 1/5000 for IgG1 titrations). Ab titers were calculated as the dilution corresponding to twice the mean absorbance value obtained for non-sensitized mouse sera. Total IgE concentrations were measured by ELISA using two monoclonal anti-IgE Abs (BD Pharmingen) as previously described (26).
Statistical analyses
Statistical significance was determined with the Statview software using Student’s t test except for chemotaxis and plethysmography data for which ANOVA for repeated measures was used. Results were expressed as mean ± SEM; p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Since DP2 is expressed on human eosinophils and basophils, besides Th2 and Tc2 lymphocytes (15), we first intended to determine whether this was also the case for mouse eosinophils. We thus analyzed, by RT-PCR, DP1 and DP2 steady-state mRNA levels in purified eosinophils, isolated from IL-5 Tg mice. Cells transfected with mouse DP1 (KmDP53) and DP2 (KmB20) cDNA were used as positive controls. Expression of both receptors was detected in eosinophils (Fig. 1A). Eosinophils appear to express greater amounts of DP1 mRNA compared with DP2 mRNA. Thus, although the lack of specific Abs did not allow us to confirm these data at the protein levels, PGD2 might act on eosinophils through activation of either DP1 or DP2.
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Since PGD2 is involved in cell chemotaxis (12, 15, 27, 28), we next examined the effects of DP1 and DP2 agonists on eosinophil migration in vitro. PGD2, BW245C (a specific DP1 agonist) or DK-PGD2 (a specific DP2 agonist) were tested for their ability to attract eosinophils. As represented in Fig. 1B, eosinophils were not only attracted by the chemokine CCL11 (used as a positive control) but also by PGD2 and DK-PGD2 in a dose-dependent manner. On the other hand, BW245C was without effect. Therefore, DP2 is functional in mouse eosinophils and promotes, as is the case in humans, eosinophil chemotaxis in vitro.
DP2 activation increases inflammation and eosinophilia in an asthma model
Having established that DP2 exerts a chemotactic activity on mouse eosinophils in vitro, we next intended to study its role in two in vivo models of allergic reactions associated to eosinophilia, namely asthma and AD. Due to the apparently antagonistic role of DP1 and DP2 (for instance on cell migration), we also studied the effect of DP1 activation in experimental asthma.
BALB/c mice were sensitized with OVA and treated by nebulization with DK-PGD2 or BW245C at the time of each Ag challenge and were compared with vehicle (DMSO)-treated animals. OVA sensitization and challenge induced eosinophilia in BAL and lung tissue, mainly in perivascular areas, compared with control animals (Fig. 2, A–C). In sensitized and challenged animals, treatment with DK-PGD2 further increased both BAL and tissue eosinophilia, whereas treatment with BW245C did not affect BAL eosinophilia but slightly decreased tissue inflammation and eosinophilia (Fig. 2, A–C). Interestingly, among the cytokines tested (IL-4, -5, -6, -10, -13, and IFN-
), the decreased eosinophilia observed in BW245C-treated animals was accompanied by a significant decrease in lung IL-5 content (Fig. 2D), whereas the increase in lung IL-5 content induced by DK-PGD2 was not statistically significant.
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DP2 activation increases inflammation and eosinophilia in a model of AD
We next assessed the effect of DK-PGD2 in a model mimicking human AD and based on Ag sensitization by repeated epicutaneous OVA applications in the absence of an adjuvant. This sensitization not only leads to the development of skin inflammation (Fig. 4A), characterized by epidermal thickening (Fig. 4B), hyperkeratosis, spongiosis, and dermal inflammatory infiltrates (Fig. 4C), but also to Ag-specific IgE and IgG1 production. DK-PGD2, topically delivered at the time of each sensitization, significantly exacerbated the pathology but had little if any effect in non-sensitized mice. Indeed, DK-PGD2 treatment increased OVA-induced inflammation (Fig. 4A), epidermal thickening (Fig. 4B), and dermal infiltrates of mast cells and eosinophils (Fig. 4C), compared with untreated sensitized mice. Likewise, compared with untreated animals, DK-PGD2 significantly increased the Th2-associated humoral response as reflected by higher levels of total and OVA-specific IgE and OVA-specific IgG1 (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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We have first demonstrated that mouse eosinophils express DP2 mRNA and provided evidences that DP2 activation induces their migration in vitro. This confirms data obtained with human cells (15, 16, 30, 31) but contrasts with a recent study claiming that DP2 is inactive in murine eosinophils, at least in terms of cell migration (32). This discrepancy might be explained by differences in the animals models (IL-5 Tg mice) used for eosinophil purification (cadmium-induced metallothionein-driven ubiquitous expression (33) vs CD2-driven T cell-specific expression in this study (21)) and/or in cell purification protocol (positive selection vs negative selection in our case). Nevertheless, mouse DP2 signal transduction pathways and biological effects appear similar to those involved in the workings of human DP2 (32). Indeed, ligand binding to the mouse DP2 induces Ca2+ mobilization and activation is sensitive to Bordetella pertussis toxin but not to cholera toxin, thus pointing toward receptor coupling to Gi proteins (32).
More importantly, we show for the first time that DP2 activation in vivo promotes eosinophilia and exacerbates pathology in two models of Th2-related inflammation: allergic asthma and AD.
The mechanisms accounting for DK-PGD2 action in vivo remain unclear, although they likely involve a direct chemotactic effect on eosinophils. This direct effect is of particular relevance in asthma since it has recently been demonstrated, using two strains of eosinophil-deficient mice, that this cell type was crucial to the development of airway remodeling (34, 35) and, according to one report, to airway hyperreactivity (34). As various cell types express DP2 in mouse, DK-PGD2 might also act on other cell populations such as T lymphocytes, as suggested by the slight increase in IL-5 in the lungs. Indeed, in humans, DP2 engagement appears to promote T cell activation and Th2-type cytokine release (36). However, such a finding has not yet been formally demonstrated in mice. Moreover, PGD2 has recently been shown to activate airway epithelial cells to produce macrophage-derived chemokine, which in turn favors pulmonary eosinophilia and AHR (36). DP2 activation in airway epithelial cells might possibly account for this phenomenon. Finally, mast cells express DP2 mRNA (data not shown), and their number is increased by DK-PGD2 in the AD model. It is possible that DP2 is active in cutaneous mast cells. Production of Ag-specific Abs is another key parameter of allergic pathologies that was increased by DK-PGD2 treatment in the AD model but not in asthma. This probably reflects the fact that animals were treated over the entire duration of the experimental protocol in AD and only during the challenge phase in asthma. DP2 activation during the early phases of the immune response might indeed impact on DC functions and/or promote the recruitment of DC progenitors to peripheral sites, as recently suggested (12).
The role of DP1 in Th2-related inflammatory reactions remains controversial. DP1-deficient mice have been shown to display decreased eosinophilia in an asthma model (37) and a new DP1 antagonist has been shown to decrease eosinophilia in a guinea pig model of allergic rhinitis (38). By contrast, our present results show that DP1 activation decreases eosinophilia and AHR in murine asthma. These apparently conflicting results on DP1 functions in the control of Th2-associated inflammation might be due to differences between animal species or mouse strain and/or between experimental approach to study DP1 (genetic inactivation in the whole animal vs airway targeting by aerosol treatment with agonist/antagonist). Finally, timing of DP1 activation might be of particular importance in the subsequent development of local immune-inflammatory response. Indeed BW245C treatment during the sensitization phase reduced the ability of Ag-loaded DCs to locally activate Ag-specific T cells in both AD (18) and asthma (H. Hammad, unpublished observations) models. Whether or not DP1 activation by BW245C during the challenge phase in the present asthma model alters DC functions still needs to be addressed. Moreover, DP1 activation might also inhibit the function of other cell types as demonstrated, at least in vitro, for eosinophils, whose CCL11-driven chemotaxis was also inhibited by BW245C (data not shown).
Taken together, our data reveal an important role of DP2 in promoting Th2-associated skin and lung inflammatory responses in mouse, whereas DP1 activation leads to the opposite outcomes and contributes to counter-regulate Th2 inflammation. This suggests that DP2 antagonists might be of therapeutic interest in diseases where eosinophilia has to be prevented. The consequences of DP2 activation by endogenously produced PGD2 await further studies using DP2-deficient mice.
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Disclosures |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Acknowledgments |
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Footnotes |
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1 This work was supported by the Institut National de la Santé et de la Recherche Médicale and the Institute Pasteur de Lille. D.D. and F.T. are members of the Institut National de la Santé et de la Recherche Médicale and the Centre National de la Recherche Scientifique, respectively. 
2 Address correspondence and reprint requests to Dr. David Dombrowicz, Unité Institut National de la Santé et de la Recherche Médicale U547, Institut Pasteur de Lille, 1, rue du Professeur Calmette, BP 245, 59019 Lille cédex, France. E-mail address: david.dombrowicz{at}pasteur-lille.fr
3 Abbreviations used in this paper: AD, atopic dermatitis; AHR, airway hyperresponsiveness; Tg, transgenic; DP, D prostanoid receptor; DC, dendritic cell; DK-PGD2, 13,14-dihydro-15-keto-PGD2; BAL, bronchoalveolar lavage; MGG, May-Grunwald-Giemsa.
Received for publication June 10, 2004. Accepted for publication December 30, 2004.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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expression in the skin and circulating IgE levels in allergen-induced skin inflammation. J. Allergy Clin. Immunol. 109:106.[Medline]
and down-regulate allergic inflammation and eosinophil activation. J. Exp. Med. 198:411.
RI chain results in upregulation of FcRIII-dependent mast cell degranulation and anaphylaxis: evidence of competition between FcRI and FcRIII for limiting amounts of FcR and chains. J. Clin. Invest. 99:915.[Medline]
12-Prostaglandin J2, a plasma metabolite of prostaglandin D2, causes eosinophil mobilization from the bone marrow and primes eosinophils for chemotaxis. J. Immunol. 170:4752.This article has been cited by other articles:
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 |
|
  R. Nomiya, M. Okano, T. Fujiwara, M. Maeda, Y. Kimura, K. Kino, M. Yokoyama, H. Hirai, K. Nagata, T. Hara, et al. CRTH2 Plays an Essential Role in the Pathophysiology of Cry j 1-Induced Pollinosis in Mice J. Immunol., April 15, 2008; 180(8): 5680 - 5688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Torres, C. Paget, J. Fontaine, T. Mallevaey, T. Matsuoka, T. Maruyama, S. Narumiya, M. Capron, P. Gosset, C. Faveeuw, et al. Prostaglandin D2 Inhibits the Production of IFN-{gamma} by Invariant NK T Cells: Consequences in the Control of B16 Melanoma J. Immunol., January 15, 2008; 180(2): 783 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shiraishi, K. Asano, K. Niimi, K. Fukunaga, M. Wakaki, J. Kagyo, T. Takihara, S. Ueda, T. Nakajima, T. Oguma, et al. Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation J. Immunol., January 1, 2008; 180(1): 541 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Schratl, J. F. Royer, E. Kostenis, T. Ulven, E. M. Sturm, M. Waldhoer, G. Hoefler, R. Schuligoi, I. Th. Lippe, B. A. Peskar, et al. The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking J. Immunol., October 1, 2007; 179(7): 4792 - 4799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 D. Voehringer, N. van Rooijen, and R. M. Locksley Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages J. Leukoc. Biol., June 1, 2007; 81(6): 1434 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. De Fanis, F. Mori, R. J. Kurnat, W. K. Lee, M. Bova, N. F. Adkinson, and V. Casolaro GATA3 up-regulation associated with surface expression of CD294/CRTH2: a unique feature of human Th cells Blood, May 15, 2007; 109(10): 4343 - 4350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
 R. N. Mitchell and P. Libby Vascular Remodeling in Transplant Vasculopathy Circ. Res., April 13, 2007; 100(7): 967 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 A. Zhang, Z. Dong, and T. Yang Prostaglandin D2 inhibits TGF-beta1-induced epithelial-to-mesenchymal transition in MDCK cells Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1332 - F1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Roosterman, T. Goerge, S. W. Schneider, N. W. Bunnett, and M. Steinhoff Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev, October 1, 2006; 86(4): 1309 - 1379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 K. Aritake, Y. Kado, T. Inoue, M. Miyano, and Y. Urade Structural and Functional Characterization of HQL-79, an Orally Selective Inhibitor of Human Hematopoietic Prostaglandin D Synthase J. Biol. Chem., June 2, 2006; 281(22): 15277 - 15286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 K. Shimizu, R. N. Mitchell, and P. Libby Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 987 - 994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
Y. Kobayashi, S. Ueki, G. Mahemuti, T. Chiba, H. Oyamada, N. Saito, A. Kanda, H. Kayaba, and J. Chihara Physiological Levels of 15-Deoxy-{Delta}12,14-Prostaglandin J2 Prime Eotaxin-Induced Chemotaxis on Human Eosinophils through Peroxisome Proliferator-Activated Receptor-{gamma} Ligation J. Immunol., November 1, 2005; 175(9): 5744 - 5750. [Abstract] [Full Text] [PDF]
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