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CRTH2 Plays an Essential Role in the Pathophysiology of Cry j 1-Induced Pollinosis in Mice¹

Rie Nomiya^*, Mitsuhiro Okano^*, Tazuko Fujiwara^*, Megumi Maeda, Yoshinobu Kimura, Kosuke Kino, Minehiko Yokoyama, Hiroyuki Hirai, Kinya Nagata, Toshifumi Hara^¶, Kazunori Nishizaki^* and Masataka Nakamura^2,¶

^* Department of Otolaryngology–Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Division of Biomolecular Science, The Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan: Meiji Company, Odawara, Japan: Department of Advanced Medicine and Development, BioMedical Laboratories, Saitama, Japan; and ^¶ Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan

PGD₂ is the major prostanoid produced during the acute phase of allergic reactions. Two PGD₂ receptors have been isolated, DP and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), but whether they participate in the pathophysiology of allergic diseases remains unclear. We investigated the role of CRTH2 in the initiation of allergic rhinitis in mice. First, we developed a novel murine model of pollinosis, a type of seasonal allergic rhinitis. Additionally, pathophysiological differences in the pollinosis were compared between wild-type and CRTH2 gene-deficient mice. An effect of treatment with ramatroban, a CRTH2/T-prostanoid receptor dual antagonist, was also determined. Repeated intranasal sensitization with Cry j 1, the major allergen of Cryptomeria japonica pollen, in the absence of adjuvants significantly exacerbated nasal hyperresponsive symptoms, Cry j 1-specific IgE and IgG1 production, nasal eosinophilia, and Cry j 1-induced in vitro production of IL-4 and IL-5 by submandibular lymph node cells. Additionally, CRTH2 mRNA in nasal mucosa was significantly elevated in Cry j 1-sensitized mice. Following repeated intranasal sensitization with Cry j 1, CRTH2 gene-deficient mice had significantly weaker Cry j 1-specific IgE/IgG1 production, nasal eosinophilia, and IL-4 production by submandibular lymph node cells than did wild-type mice. Similar results were found in mice treated with ramatroban. These results suggest that the PGD₂-CRTH2 interaction is elevated following sensitization and plays a proinflammatory role in the pathophysiology of allergic rhinitis, especially pollinosis in mice.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (14704143), and Research on Allergic Disease and Immunology of the Ministry of Health, Labor, and Welfare, Japan (14210301).

² Address correspondence and reprint requests to Dr. Mitsuhiro Okano, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikatacho, 700-8558 Okayama, Japan. E-mail address: mokano{at}cc.okayama-u.ac.jp

³ Abbreviations used in this paper: JCP, Japanese cedar pollinosis; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; DP, D-protanoid receptor; TP, T-prostanoid receptor; WT, wild type.

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