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Enhanced Th2 Cell Differentiation and Allergen-Induced Airway Inflammation in Zfp35-Deficient Mice¹

Masayuki Kitajima,^* Chiaki Iwamura,^* Takako Miki-Hosokawa,^* Kenta Shinoda,^* Yusuke Endo,^* Yukiko Watanabe,^* Ryo Shinnakasu,^* Hiroyuki Hosokawa,^* Kahoko Hashimoto, Shinichiro Motohashi,^* Haruhiko Koseki, Osamu Ohara, Masakatsu Yamashita,^* and Toshinori Nakayama^2*

^*Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Life and Environmental Sciences and High Technology Research Center, Chiba Institute of Technology, Naraschino, Tsudanuma, Chiba, Japan; and Laboratory for Developmental Genetics and Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

Studies of human asthma and of animal models of allergic airway inflammation revealed a crucial role for Th2 cells in the pathogenesis of allergic asthma. Kruppel-type zinc finger proteins are the largest family of a regulatory transcription factor for cellular development and function. Zinc finger protein (Zfp) 35 is an 18-zinc finger motif-containing Kruppel-type zinc finger protein, while its function remains largely unknown. The aim of this study was to clarify the role of Zfp35 in the pathogenesis of Th2-dependent allergic inflammation, such as allergic asthma. We examined airway eosinophilic inflammation and hyperresponsiveness in two mouse models, which use our newly generated Zfp35-deficient (Zfp35^–/–) mice and adoptive transfer of cells. In Zfp35^–/– mice, Th2 cell differentiation, Th2 cytokine production, eosinophilic inflammation, and airway hyperresponsiveness were substantially enhanced. Furthermore, adoptive transfer of Ag-sensitized Zfp35^–/– CD4 T cells into the asthmatic mice resulted in enhanced airway inflammation and airway hyperresponsiveness. These results indicate that Zfp35 controls Th2 cell differentiation, allergic airway inflammation, and airway hyperresponsiveness in a negative manner. Thus, Zfp35 may control Th2-dependent diseases, such as allergic asthma.

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 by the Global Center for Education Program (Global Center for Education and Research in Immune System Regulation and Treatment), Monbukagakusho (Japan), and by grants from the Ministry of Education, Culture, Sports, Science and Technology (Japan) (Grants-in-Aid for Scientific Research on Priority Areas no. 17016010 and no. 20060003; Scientific Research (B) no. 21390147, Scientific Research (C) no. 21591808 and no. 20590485, and Young Scientists (B) no. 20790367; and Start-up no. 20890038: Cancer Translational Research Project), the Ministry of Health, Labor and Welfare (Japan), and The Japan Health Science Foundation, Kanae Foundation, and Uehara Memorial Foundation.

² Address correspondence and reprint requests to Dr. Toshinori Nakayama, Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail address: tnakayama{at}faculty.chiba-u.jp

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; EPO, eosinophil peroxidase; Zfp, zinc finger protein; Tg, transgenic; RL, lung resistance.