Psoriasis is a T-cell-mediated immunological skin disease with a complex pathogenesis where both genetic and environmental factors are involved. Interferon (IFN) regulatory factor (IRF)-2 is one of the potential susceptibility genes for psoriasis. IRFs are a family of transcription factors that regulate expression of pro- and anti-inflammatory genes. IRF-2 protein binds the same regulatory sequence as IRF-1, which suppresses transcription of IFN-inducible genes. Topical application of imiquimod(IMQ), a TLR7/8 ligand, induces psoriasis-like inflamed skin lesions via the IL-17/23 axis. We hypothesized that combination of IRF2 gene status and environmental stimulus (IMQ) would cause severer skin lesions, serving as a good model of human psoriasis. IMQ-induced skin inflammation assessed by erythema, scaling, and skin thickness was severer in IRF-2+/- mice than WT mice. In inflamed skin, mRNA expression of TNF-α, IL-12/23p40, IL-23p19, and inducible nitric oxide synthase (iNOS) was increased on day 2, and that of TNF-α, IL-12p35, IL-17A, and iNOS was increased on day 5 in IRF-2+/- mice compared to WT mice. In peritoneal macrophage of IRF-2+/- and WT mice stimulated with IMQ, mRNA levels of TNF-α, IL-12/23p40, IL-23p19, IL-12p35, and IL-36 were significantly elevated compared to non-stimulated macrophages. IFN-α expression was not induced by IMQ. Interestingly, macrophages from IRF-2+/- mice expressed higher levels of TNF-α, IL-12/23p40, and IL-36 compared to those from WT mice 24 hours after stimulation, while they expressed similar levels of IL-12p35 and IL-23p19. Moreover, elevated mRNA expression of iNOS was observed only in stimulated macrophages derived from IRF-2+/- mice. Stimulation with IFN-α dose-dependently increased expression levels of TNF-α, IL-12/23p40, IL-36, and iNOS, but not IL-12p35 or IL-23p19, from peritoneal macrophages. These results suggest that IRF-2 haploinsufficiency caused hypersensitivity to IFN-α, and that a TLR7/8 stimulator developed enhanced Th17-associated skin inflammation, which may serve as a good model of human psoriasis.