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 cd-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 proinflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7 À/À 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)-a, IL-23, IL-6 and tumor necrosis factor (TNF)-a. Furthermore, when we analyzed in vitro-generated bone marrow-derived DCs with features similar to TNF-a and inducible nitric oxide synthase (iNOS)-producing DCs, IL-23, IL-6, IL-1b, TNF-a and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co-stimulation with IMQ and IFN-a. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN-a was suggested to be caused by upregulation of TLR7 expression by IFN-a. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasislike skin inflammation are induced by IMQ and IFN-a in a mouse model.
We have previously reported that S-777469 [1-([6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl]amino)-cyclohexanecarboxylic acid], a novel cannabinoid type 2 receptor (CB2) agonist, significantly suppressed compound 48/80-induced scratching behavior in mice in a dose-dependent manner when it was administered orally. Here, we demonstrated that the inhibitory effects of S-777469 on compound 48/80-induced scratching behavior are reversed by pretreatment with SR144528, a CB2-selective antagonist. In addition, we investigated the effects of S-777469 on itch-associated scratching behavior induced by several pruritogenic agents in mice and rats. S-777469 significantly suppressed scratching behavior induced by histamine or substance P in mice or by serotonin in rats. In contrast, the H1-antihistamine fexofenadine clearly inhibited histamine-induced scratching behavior but did not affect scratching behavior induced by substance P or serotonin. Moreover, S-777469 significantly inhibited histamine-induced peripheral nerve firing in mice. In conclusion, these results suggest that S-777469 produces its antipruritic effects by inhibiting itch signal transmission through CB2 agonism.
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