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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.

the journal of immunology/the journal of immunology

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