title: Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod.
abstract: Topical application of imiquimod (IMQ), a Toll-like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ-induced psoriasis-like skin inflammation, T-helper (Th)17 cells and interleukin (IL)-17/IL-22-producing γδ-T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis-like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ-induced psoriasis-like skin inflammation in mice. We first confirmed that, together with an increase in IL-17 and IL-22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and pro-inflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7(-/-) mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)-α, IL-23, IL-6 and tumor necrosis factor (TNF)-α. Furthermore, when we analyzed in vitro-generated bone marrow-derived DCs with features similar to TNF-α and inducible nitric oxide synthase (iNOS)-producing DCs, IL-23, IL-6, IL-1β, TNF-α and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co-stimulation with IMQ and IFN-α. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN-α was suggested to be caused by upregulation of TLR7 expression by IFN-α. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasis-like skin inflammation are induced by IMQ and IFN-α in a mouse model.
authors.affiliation: Medicinal Research Laboratories, Shionogi, Toyonaka, Japan.
authors.forename: Azumi
authors.initials: A
authors.lastname: Ueyama
authors.forename: Mina
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Tsujii
authors.forename: Yoko
authors.initials: Y
authors.lastname: Furue
authors.forename: Chihiro
authors.initials: C
authors.lastname: Imura
authors.forename: Michitaka
authors.initials: M
authors.lastname: Shichijo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yasui
mesh_terms: D000634:Aminoquinolines / Q000009:adverse effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects*; D003875:Drug Eruptions / Q000276:immunology* / Q000378:metabolism; D000077271:Imiquimod; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016207:Cytokines; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000077271:Imiquimod
keywords: T-helper 17; Toll-like receptor 7; plasmacytoid dendritic cell; psoriasis; tumor necrosis factor-α and inducible NO synthetase producing dendritic cells