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Science 287 (5460): 2013-2017

Copyright © 2000 by the American Association for the Advancement of Science

Prostaglandin D2 as a Mediator of Allergic Asthma

Toshiyuki Matsuoka, 12 Masakazu Hirata, 1 Hiroyuki Tanaka, 3 Yoshimasa Takahashi, 3 Takahiko Murata, 1 Kenji Kabashima, 1 Yukihiko Sugimoto, 4 Takuya Kobayashi, 1 Fumitaka Ushikubi, 1 Yoshiya Aze, 5 Naomi Eguchi, 6 Yoshihiro Urade, 6 Nobuaki Yoshida, 7 Kazushi Kimura, 8 Akira Mizoguchi, 8 Yoshihito Honda, 2 Hiroichi Nagai, 3 Shuh Narumiya 1*

Allergic asthma is caused by the aberrant expansion in the lung of T helper cells that produce type 2 (TH2) cytokines and is characterized by infiltration of eosinophils and bronchial hyperreactivity. This disease is often triggered by mast cells activated by immunoglobulin E (IgE)-mediated allergic challenge. Activated mast cells release various chemical mediators, including prostaglandin D2 (PGD2), whose role in allergic asthma has now been investigated by the generation of mice deficient in the PGD receptor (DP). Sensitization and aerosol challenge of the homozygous mutant (DP-/-) mice with ovalbumin (OVA) induced increases in the serum concentration of IgE similar to those in wild-type mice subjected to this model of asthma. However, the concentrations of TH2 cytokines and the extent of lymphocyte accumulation in the lung of OVA-challenged DP-/- mice were greatly reduced compared with those in wild-type animals. Moreover, DP-/- mice showed only marginal infiltration of eosinophils and failed to develop airway hyperreactivity. Thus, PGD2 functions as a mast cell-derived mediator to trigger asthmatic responses.

1 Department of Pharmacology,
2 Department of Ophthalmology, and
8 Department of Anatomy, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan.
3 Department of Pharmacology, Gifu Pharmaceutical University, Gifu 502-0003, Japan.
4 Department of Physiological Chemistry, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto 606-8501, Japan.
5 Fukui Safety Research Laboratories, Ono Pharmaceutical Company, Fukui 913-8538, Japan.
6 Osaka Bioscience Institute, Osaka 565-0874, Japan.
7 Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
*   To whom correspondence should be addressed. Department of Pharmacology, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: snaru{at}mfour.med.kyoto-u.ac.jp

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Uteroglobin Represses Allergen-induced Inflammatory Response by Blocking PGD2 Receptor-mediated Functions.
A. K. Mandal, Z. Zhang, R. Ray, M. S. Choi, B. Chowdhury, N. Pattabiraman, and A. B. Mukherjee (2004)
J. Exp. Med. 199, 1317-1330
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Activation of the D Prostanoid Receptor 1 Regulates Immune and Skin Allergic Responses.
V. Angeli, D. Staumont, A.-S. Charbonnier, H. Hammad, P. Gosset, M. Pichavant, B. N. Lambrecht, M. Capron, D. Dombrowicz, and F. Trottein (2004)
J. Immunol. 172, 3822-3829
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First Determination of the Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase.
T. Inoue, Y. Okano, Y. Kado, K. Aritake, D. Irikura, N. Uodome, N. Okazaki, S. Kinugasa, H. Shishitani, H. Matsumura, et al. (2004)
J. Biochem. 135, 279-283
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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.
M. Shichijo, H. Sugimoto, K. Nagao, H. Inbe, J. A. Encinas, K. Takeshita, K. B. Bacon, and F. Gantner (2003)
J. Pharmacol. Exp. Ther. 307, 518-525
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Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide.
K Arai, T Ohno, T Saeki, S Mizuguchi, K Kamata, I Hayashi, K Saigenji, T Murata, S Narumiya, and M Majima (2003)
Gut 52, 1242-1249
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Specific Regulation of Lipocalin-Type Prostaglandin D Synthase in Mouse Heart by Estrogen Receptor {beta}.
M. Otsuki, H. Gao, K. Dahlman-Wright, C. Ohlsson, N. Eguchi, Y. Urade, and J.-A. Gustafsson (2003)
Mol. Endocrinol. 17, 1844-1855
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Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine.
K. Honda, M. Arima, G. Cheng, S. Taki, H. Hirata, F. Eda, F. Fukushima, B. Yamaguchi, M. Hatano, T. Tokuhisa, et al. (2003)
J. Exp. Med. 198, 533-543
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Expression and Molecular Pharmacology of the Mouse CRTH2 Receptor.
A. N. Hata, R. Zent, M. D. Breyer, and R. M. Breyer (2003)
J. Pharmacol. Exp. Ther. 306, 463-470
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Production of Eicosanoids and Other Oxylipins by Pathogenic Eukaryotic Microbes.
M. C. Noverr, J. R. Erb-Downward, and G. B. Huffnagle (2003)
Clin. Microbiol. Rev. 16, 517-533
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Prostaglandin D2 Synthase Inhibits the Exaggerated Growth Phenotype of Spontaneously Hypertensive Rat Vascular Smooth Muscle Cells.
L. Ragolia, T. Palaia, E. Paric, and J. K. Maesaka (2003)
J. Biol. Chem. 278, 22175-22181
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Prostaglandin D2 Affects the Maturation of Human Monocyte-Derived Dendritic Cells: Consequence on the Polarization of Naive Th Cells.
P. Gosset, F. Bureau, V. Angeli, M. Pichavant, C. Faveeuw, A.-B. Tonnel, and F. Trottein (2003)
J. Immunol. 170, 4943-4952
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Retrovirally Introduced Prostaglandin D2 Synthase Suppresses Lung Injury Induced by Bleomycin.
M. Ando, Y. Murakami, F. Kojima, H. Endo, H. Kitasato, A. Hashimoto, H. Kobayashi, M. Majima, M. Inoue, H. Kondo, et al. (2003)
28, 582-591
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{Delta}12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis.
A. Heinemann, R. Schuligoi, I. Sabroe, A. Hartnell, and B. A. Peskar (2003)
J. Immunol. 170, 4752-4758
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Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes.
Y. Matsuoka, T. Furuyashiki, H. Bito, F. Ushikubi, Y. Tanaka, T. Kobayashi, S. Muro, N. Satoh, T. Kayahara, M. Higashi, et al. (2003)
PNAS 100, 4132-4137
   Abstract »    Full Text »    PDF »
Role of PLB1 in Pulmonary Inflammation and Cryptococcal Eicosanoid Production.
M. C. Noverr, G. M. Cox, J. R. Perfect, and G. B. Huffnagle (2003)
Infect. Immun. 71, 1538-1547
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Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination.
R. Pedotti, J. J. DeVoss, S. Youssef, D. Mitchell, J. Wedemeyer, R. Madanat, H. Garren, P. Fontoura, M. Tsai, S. J. Galli, et al. (2003)
PNAS 100, 1867-1872
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RasGRP4 Regulates the Expression of Prostaglandin D2 in Human and Rat Mast Cell Lines.
L. Li, Y. Yang, and R. L. Stevens (2003)
J. Biol. Chem. 278, 4725-4729
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Characterization of the Unfolding Process of Lipocalin-type Prostaglandin D Synthase.
T. Inui, T. Ohkubo, M. Emi, D. Irikura, O. Hayaishi, and Y. Urade (2003)
J. Biol. Chem. 278, 2845-2852
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Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth.
H. Amano, I. Hayashi, H. Endo, H. Kitasato, S. Yamashina, T. Maruyama, M. Kobayashi, K. Satoh, M. Narita, Y. Sugimoto, et al. (2003)
J. Exp. Med. 197, 221-232
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15R-Methyl-Prostaglandin D2 Is a Potent and Selective CRTH2/DP2 Receptor Agonist in Human Eosinophils.
G. Monneret, C. Cossette, S. Gravel, J. Rokach, and W. S. Powell (2003)
J. Pharmacol. Exp. Ther. 304, 349-355
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Cloning, Expression, Crystallization, and Preliminary X-Ray Analysis of Recombinant Mouse Lipocalin-type Prostaglandin D Synthase, a Somnogen-Producing Enzyme.
D. Irikura, T. Kumasaka, M. Yamamoto, H. Ago, M. Miyano, K. B. Kubata, H. Sakai, O. Hayaishi, and Y. Urade (2003)
J. Biochem. 133, 29-32
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PGD2 Modulates Fibroblast-Mediated Native Collagen Gel Contraction.
T. Kohyama, T. A. Wyatt, X. Liu, F.-Q. Wen, T. Kobayashi, Q. Fang, H. J. Kim, and S. I. Rennard (2002)
27, 375-381
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Retinal Capillary Pericyte Proliferation and c-Fos mRNA Induction by Prostaglandin D2 through the cAMP Response Element.
S. Sakurai, S. Alam, G. Pagan-Mercado, F. Hickman, J.-Y. Tsai, P. Zelenka, and S. Sato (2002)
Invest. Ophthalmol. Vis. Sci. 43, 2774-2781
   Abstract »    Full Text »    PDF »
Open Mind, Open Airways . Broadening the Paradigm of Prostaglandins and Allergic Airway Inflammation.
M. Peters-Golden (2002)
165, 1035-1036
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