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

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 AFN-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-a/IFN-0 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 AFN-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-a/IFN-1; 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-T 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.