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IFN- Attenuates Antigen-Induced Overall Immune Response in the Airway As a Th1-Type Immune Regulatory Cytokine¹

Kazuyuki Nakagome^*, Katsuhide Okunishi^*, Mitsuru Imamura^*, Hiroaki Harada^*, Taku Matsumoto^*, Ryoichi Tanaka^*, Jun-ichi Miyazaki, Kazuhiko Yamamoto^* and Makoto Dohi^2,*

^* Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, and Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan

Allergic inflammation in the airway is generally considered a Th2-type immune response. However, recent studies demonstrated that Th1- and Th17-type immune responses also play important roles in this process. IFN- is a Th1-type cytokine that generally counteracts the Th2 response. Although previous studies suggest that exogenous IFN- suppresses allergic airway inflammation, the mechanism of suppression has not been fully clarified. In this study, we elucidated whether IFN- suppresses Ag-induced immune responses including the production of Th1- and Th17-type cytokines in the lung, and examined its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IFN--producing plasmid vector was delivered before systemic Ag sensitization. IFN- suppressed indicators of Th2-type immune responses such as airway eosinophilia, IL-5 and IL-13 production in the lung, and bronchial mucus production. Moreover, IFN- also suppressed the production of IL-17 and IFN- itself. The suppression was not mediated by inducing regulatory T cells or by inducing apoptosis in immunocytes. Instead, IFN- suppressed the Ag-presenting capacity and cytokine production of splenic dendritic cells and thus subsequently suppressed OVA-induced activation of CD4⁺ T cells. Furthermore, IFN- also attenuated allergic airway inflammation when delivered during the OVA challenge. Various functions of lung CD11c⁺ APCs and their migration to regional lymph nodes were also suppressed. These results suggest that the Th1 cytokine IFN- has broad immune regulatory potential through suppressing APC functions. They also suggest that delivery of IFN- could be an effective strategy for regulating Ag-induced immune responses in the lung.

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 Grant-in-aid 17590782 from the Ministry of Health, Welfare, and Labor of Japan.

² Address correspondence and reprint requests to Dr. Makoto Dohi, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail address: mdohi-tky{at}umin.ac.jp

³ Abbreviations used in this paper: Treg, regulatory T; alum, aluminum hydroxide; SA, physiologic saline; BALF, bronchoalveolar lavage fluid; DC, dendritic cell; PI, propidium iodide; IP-10, IFN--inducing protein 10.