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Genetic Control Directed toward Spontaneous IFN-/IFN-β Responses and Downstream IFN- Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease¹

Fuyuko Arakura^*,, Shigeaki Hida^*, Eri Ichikawa^*, Chihiro Yajima^*, Shinsuke Nakajima^*, Toshiaki Saida and Shinsuke Taki^2,*

^* Department of Immunology and Infectious Diseases, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; and Department of Dermatology, School of Medicine, Shinshu University, Matsumoto, Japan

Psoriasis is an inflammatory skin disease, onset and severity of which are controlled by multiple genetic factors; aberrant expression of and responses to several cytokines including IFN-/IFN-β and IFN- are associated with this "type 1" disease. However, it remains unclear whether genetic regulation influences these cytokine-related abnormalities. Mice deficient for IFN regulatory factor-2 (IRF-2) on the C57BL/6 background (IRF-2^–/–BN mice) exhibited accelerated IFN-/IFN-β responses leading to a psoriasis-like skin inflammation. In this study, we found that this skin phenotype disappeared in IRF-2^–/– mice with the BALB/c or BALB/c x C57BL/6 F₁ backgrounds. Genome-wide scan revealed two major quantitative trait loci controlled the skin disease severity. Interestingly, these loci were different from that for the defect in CD4⁺ dendritic cells, another IFN-/IFN-β-dependent phenotype of the mice. Notably, IFN- expression as well as spontaneous IFN-/IFN-β responses were up-regulated several fold spontaneously in the skin in IRF-2^–/–BN mice but not in IRF-2^–/– mice with "resistant" backgrounds. The absence of such IFN- up-regulation in IRF-2^–/–BN mice lacking the IFN-/IFN-β receptor or β₂-microglobulin indicated that accelerated IFN-/IFN-β signals augmented IFN- expression by CD8⁺ T cells in the skin. IFN- indeed played pathogenic roles as skin inflammation was delayed and was much more infrequent when IRF-2^–/–BN mice lacked the IFN- receptor. Our current study thus revealed a novel genetic mechanism that kept the skin immune system under control and prevented skin inflammation through regulating the magnitude of IFN-/IFN-β responses and downstream IFN- production, independently of CD4⁺ dendritic cells.

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 a Grant-in-Aid for Scientific Research on Priority Area (18060016) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid (19590494) from the Japan Science Promotion Society, and a grant from the Naito Foundation.

² Address correspondence and reprint requests to Dr. Shinsuke Taki, Department of Immunology and Infectious Diseases, Graduate School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail address: shin-t{at}sch.md.shinshu-u.ac.jp

³ Abbreviations used in this paper: IRF-2, IFN regulatory factor-2; DC, dendritic cell; QTL, quantitative trait locus; LRS, likelihood ratio statistics; LOD, logarithm of the odds; β₂m, β₂-microglobulin.

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The JI 2007 179: 2665-2666. [Full Text]