title: Genetic control directed toward spontaneous IFN-alpha/IFN-beta responses and downstream IFN-gamma expression influences the pathogenesis of a murine psoriasis-like skin disease.
abstract: 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-alpha/IFN-beta and IFN-gamma 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-alpha/IFN-beta 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 F(1) 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-alpha/IFN-beta-dependent phenotype of the mice. Notably, IFN-gamma expression as well as spontaneous IFN-alpha/IFN-beta 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-gamma up-regulation in IRF-2(-/-)BN mice lacking the IFN-alpha/IFN-beta receptor or beta(2)-microglobulin indicated that accelerated IFN-alpha/IFN-beta signals augmented IFN-gamma expression by CD8(+) T cells in the skin. IFN-gamma indeed played pathogenic roles as skin inflammation was delayed and was much more infrequent when IRF-2(-/-)BN mice lacked the IFN-gamma 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-alpha/IFN-beta responses and downstream IFN-gamma production, independently of CD4(+) dendritic cells.
authors: Department of Immunology and Infectious Diseases, Graduate School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors: Fuyuko
authors: F
authors: Arakura
authors: Shigeaki
authors: S
authors: Hida
authors: Eri
authors: E
authors: Ichikawa
authors: Chihiro
authors: C
authors: Yajima
authors: Shinsuke
authors: S
authors: Nakajima
authors: Toshiaki
authors: T
authors: Saida
authors: Shinsuke
authors: S
authors: Taki
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D050836:Interferon Regulatory Factor-2 / Q000235:genetics*; D016898:Interferon-alpha / Q000235:genetics; D016899:Interferon-beta / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D007372:Interferons / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D011565:Psoriasis / Q000235:genetics* / Q000473:pathology; D040641:Quantitative Trait Loci; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology; D015854:Up-Regulation
chemical_list: D015704:CD4 Antigens; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha; C494230:Irf2 protein, mouse; D016899:Interferon-beta; D007371:Interferon-gamma; D007372:Interferons