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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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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)
Am. J. Respir. Cell Mol. Biol. 27, 375-381
   Abstract »    Full Text »    PDF »
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)
Am. J. Respir. Crit. Care Med. 165, 1035-1036
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Selective Cyclooxygenase-1 and -2 Inhibitors Each Increase Allergic Inflammation and Airway Hyperresponsiveness in Mice.
R. Stokes Peebles Jr., K. Hashimoto, J. D. Morrow, R. Dworski, R. D. Collins, Y. Hashimoto, J. W. Christman, K.-H. Kang, K. Jarzecka, J. Furlong, et al. (2002)
Am. J. Respir. Crit. Care Med. 165, 1154-1160
   Abstract »    Full Text »    PDF »
15-Deoxy-{Delta}12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils.
G. Monneret, H. Li, J. Vasilescu, J. Rokach, and W. S. Powell (2002)
J. Immunol. 168, 3563-3569
   Abstract »    Full Text »    PDF »
Functional Genomics of Sleep and Circadian Rhythm: Invited Review: Molecular genetic studies on sleep-wake regulation, with special emphasis on the prostaglandin D2 system.
O. Hayaishi (2002)
J Appl Physiol 92, 863-868
   Abstract »    Full Text »    PDF »
The Th2 Lymphocyte Products IL-4 and IL-13 Rapidly Induce Airway Hyperresponsiveness Through Direct Effects on Resident Airway Cells.
R. Venkayya, M. Lam, M. Willkom, G. Grunig, D. B. Corry, and D. J. Erle (2002)
Am. J. Respir. Cell Mol. Biol. 26, 202-208
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Cyclooxygenase-2 Expression during Allergic Inflammation in Guinea-Pig Lungs.
T. OGUMA, K. ASANO, T. SHIOMI, K. FUKUNAGA, Y. SUZUKI, M. NAKAMURA, H. MATSUBARA, H. K. SHELDON, K. J. HALEY, C. M. LILLY, et al. (2002)
Am. J. Respir. Crit. Care Med. 165, 382-386
   Abstract »    Full Text »    PDF »
Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2.
H. Hirai, K. Tanaka, S. Takano, M. Ichimasa, M. Nakamura, and K. Nagata (2002)
J. Immunol. 168, 981-985
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Regulation of Prostaglandin Endoperoxide Synthase-2 and IL-6 Expression in Mouse Bone Marrow-Derived Mast Cells by Exogenous But Not Endogenous Prostanoids.
B. L. Diaz, H. Fujishima, Y. Kanaoka, Y. Urade, and J. P. Arm (2002)
J. Immunol. 168, 1397-1404
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Lipocalin-Type Prostaglandin D Synthase in Essential Hypertension.
N. Hirawa, Y. Uehara, M. Yamakado, Y. Toya, T. Gomi, T. Ikeda, Y. Eguchi, M. Takagi, H. Oda, K. Seiki, et al. (2002)
Hypertension 39, 449-454
   Abstract »    Full Text »    PDF »
Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis.
I. R. Adams and A. McLaren (2002)
Development 129, 1155-1164
   Abstract »    Full Text »    PDF »
Production of Prostaglandins and Leukotrienes by Pathogenic Fungi.
M. C. Noverr, G. B. Toews, and G. B. Huffnagle (2002)
Infect. Immun. 70, 400-402
   Abstract »    Full Text »    PDF »
Involvement of Prostaglandin E Receptor Subtype EP4 in Colon Carcinogenesis.
M. Mutoh, K. Watanabe, T. Kitamura, Y. Shoji, M. Takahashi, T. Kawamori, K. Tani, M. Kobayashi, T. Maruyama, K. Kobayashi, et al. (2002)
Cancer Res. 62, 28-32
   Abstract »    Full Text »    PDF »
Pronounced Eosinophilic Lung Inflammation and Th2 Cytokine Release in Human Lipocalin-Type Prostaglandin D Synthase Transgenic Mice.
Y. Fujitani, Y. Kanaoka, K. Aritake, N. Uodome, K. Okazaki-Hatake, and Y. Urade (2002)
J. Immunol. 168, 443-449
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CTLA4-IgG Reverses Asthma Manifestations in a Mild but Not in a More ""Severe"" Ongoing Murine Model.
D. T. Deurloo, B. C.A.M. van Esch, C. L. Hofstra, F. P. Nijkamp, and A. J.M. van Oosterhout (2001)
Am. J. Respir. Cell Mol. Biol. 25, 751-760
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Leukotriene and Prostanoid Pathway Enzymes in Bronchial Biopsies of Seasonal Allergic Asthmatics.
M. L. SEYMOUR, S. RAK, D. ABERG, G. C. RIISE, J. F. PENROSE, Y. KANAOKA, K. F. AUSTEN, S. T. HOLGATE, and A. P. SAMPSON (2001)
Am. J. Respir. Crit. Care Med. 164, 2051-2056
   Abstract »    Full Text »    PDF »
Prostanoid receptors: ontogeny and implications in vascular physiology.
D. H. Wright, D. Abran, M. Bhattacharya, X. Hou, S. G. Bernier, A. Bouayad, J.-C. Fouron, A. Vazquez-Tello, M. H. Beauchamp, R. I. Clyman, et al. (2001)
Am J Physiol Regulatory Integrative Comp Physiol 281, R1343-R1360
   Abstract »    Full Text »    PDF »
PGRL Is a Major CD81-Associated Protein on Lymphocytes and Distinguishes a New Family of Cell Surface Proteins.
K. L. Clark, Z. Zeng, A. L. Langford, S. M. Bowen, and S. C. Todd (2001)
J. Immunol. 167, 5115-5121
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Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor.
G. Monneret, S. Gravel, M. Diamond, J. Rokach, and W. S. Powell (2001)
Blood 98, 1942-1948
   Abstract »    Full Text »    PDF »
Prevention of Allergic Inflammation by a Novel Prostaglandin Receptor Antagonist, S-5751.
A. Arimura, K. Yasui, J. Kishino, F. Asanuma, H. Hasegawa, S. Kakudo, M. Ohtani, and H. Arita (2001)
J. Pharmacol. Exp. Ther. 298, 411-419
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The Diverse Roles of Mast Cells.
M. F. Gurish and K. F. Austen (2001)
J. Exp. Med. 194, f1-f6
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Role of the Parasite-Derived Prostaglandin D2 in the Inhibition of Epidermal Langerhans Cell Migration during Schistosomiasis Infection.
V. Angeli, C. Faveeuw, O. Roye, J. Fontaine, E. Teissier, A. Capron, I. Wolowczuk, M. Capron, and F. Trottein (2001)
J. Exp. Med. 193, 1135-1148
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