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.

Abstract. This study investigated the involvement of tryptase and proteinase-activated receptor (PAR) subtypes in spontaneous scratching, an itch-associated behavior, in NC mice. This strain of mice showed chronic atopy-like dermatitis and severe spontaneous scratching, when kept a long time in a conventional environment. The trypsin-like serine proteinase inhibitor nafamostat mesilate (1 -10 mg/kg) dose-dependently inhibited spontaneous scratching in mice with dermatitis. The activity of tryptase was increased in the lesional skin, which was inhibited by nafamostat at a dose inhibiting spontaneous scratching. Enzyme histochemistry revealed the marked increase of toluidine blue-stained cells, probably mast cells, with tryptase activity in the dermis of the lesional skin. Intravenous injection of anti-PAR 2 antibody suppressed spontaneous scratching of mice with dermatitis. Intradermal injection of the PAR 2 -activating peptide SLI-GRL-NH 2 , but not PAR 1 , 3 , 4 -activating peptides, elicited scratching at doses of 10 -100 nmol/site in healthy mice. PAR 2 -immunoreactivity was observed in the epidermal keratinocytes in healthy and dermatitis mice. These results suggest that PAR 2 and serine proteinase(s), mainly tryptase, are involved in the itch of chronic dermatitis.

Abstract. Proteinase-activated receptor-2 (PAR 2 ) participates in itch, but the role of the other subtypes of this receptor remain unknown. To investigate this issue, scratching, an itch-related behavior, was observed following intradermal injections of the activating peptides of PAR 1-4 in mice. Activating peptides of PAR 1 , PAR 2 , and PAR 4 , but not PAR 3 , induced scratching. The antihistamine terfenadine suppressed scratching elicited by activating peptides of PAR 1 and PAR 4 , but not PAR 2 . These results suggest that PAR 1 , PAR 2 , and PAR 4 are involved in itch and that histamine is a cause of itch related to PAR 1 and PAR 4 , but not PAR 2 .

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