Itching in a trichophytin contact dermatitis mouse model and the antipruritic effect of antifungal agents.

BACKGROUND: Tinea is an infectious disease by dermatophytes, of which Trichophyton species accounts for the overwhelming majority of case. Tinea often causes itching with inflammation. In terms of pruritus by fungal infection, however, tinea has not been investigated sufficiently to date. AIM: To evaluate itch caused by Trichophyton infection and the effect of antifungal agents on the infection, by measuring scratch behaviour and profiles of inflammatory cytokines and chemokines. METHODS: We used a previously established mouse model of contact hypersensitivity induced by trichophytin, a crude extract from Trichophyton mentagrophytes. Scratching behaviour was recorded using a counting device that measured an electric current induced in a coil by movement of magnets that had been inserted into the hind paws of each animal. We investigated expression of various genes in lesional skin of mice and in normal human epidermal keratinocytes. We also investigated the antipruritic effects of the corticosteroid dexamethasone (DEX) and three antifungal agents: ketoconazole (KCZ), terbinafine (TBF) and liranaftate (LNF). RESULTS: Biphasic peaks of scratching were observed at 1 h and at 6-7 h during an observation period of 14 h after trichophytin induction. For lesional skin, RNA was extracted 24 h after trichophytin challenge, and increased expression was seen in the genes for interleukin (IL)-17A, interferon-γ, tumour necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-2 and Dectin-1, whereas there was no obvious change in the genes for IL-31 and prostaglandin (PG)E2. Furthermore, KCZ inhibited histidine decarboxylase (HDC) expression in vitro and in vivo, and inhibited scratching in the very early phase. LNF inhibited expression of thymic stromal lymphopoietin (TSLP) and IL-8 in vitro, and TSLP, TNF-α, IL-1α and MIP2 in vivo, and also scratching in the early phase. TBF did not induce any significant alterations in either gene expression or scratching. DEX suppressed expression of all the chemical mediators except HDC in vitro and in vivo, and inhibited scratching. CONCLUSION: Antifungals can inhibit itching induced by fungal infection through different mechanisms.

Overexpression of monocyte-derived cytokines in active psoriasis: a relation to coexistent arthropathy.

An overexpression of inflammatory cytokines has been found in the lesional skin as well as peripheral blood in patients with psoriasis, although its etiological significance is not yet understood. In order to evaluate the cell type responsible for the elevated cytokines in the peripheral blood, we investigated cytokine profiles of the fractionated peripheral blood mononuclear cells (PBMCs) in 30 patients with psoriasis and 27 healthy controls. Without stimulation, higher levels of interleukin (IL)-1beta, IL-6, and IL-8 were produced by freshly isolated PBMCs from the patients than those from the controls. In the fractionated PBMCs, the monocyte-rich fractions were mainly responsible for the production of these cytokines and mRNA. The elevated levels of monocyte-derived cytokine mRNAs decreased following successful treatment with cyclosporin A. Although no correlation was found between the cytokine levels and the psoriasis area and severity index (PASI) scores, patients with arthropathy showed significantly high production levels of IL-1beta, IL-6, and IL-8. These findings suggest that monocytes are the major cell source producing inflammatory cytokines in the peripheral blood of psoriasis, and the increased cytokine levels are related to the coexistent arthropathy rather than the severity of cutaneous lesions.

Interleukin-15 is not a constitutive cytokine in the epidermis, but is inducible in culture or inflammatory conditions.

The regulation in the skin of interleukin-15 (IL-15), a potent modulator of T-cell-mediated immune responses, is not fully understood. We investigated the levels of IL-15 and its mRNA produced by epidermal and cultured keratinocytes and found that normal keratinocytes did not constitutively express IL-15 in the epidermis, but in culture began to produce the cytokine. Some epidermal keratinocytes expressed IL-15 in inflammatory conditions associated with infiltration of neutrophils and eosinophils. IL-15 was detected only in the cell lysates, not in the supernatants of cultured keratinocytes. Dexamethasone (10(-5)-10(-6) M) markedly inhibited IL-15 mRNA expression by normal and transformed keratinocytes in a range of pharmacological concentrations. IFN-gamma (200 and 400 U/ml) slightly increased the IL-15 message level in a squamous cell carcinoma cell line, HSC-5, in a dose-dependent fashion, whereas no significant change was observed in cultured normal human keratinocytes. Our data indicate that IL-15 is not a constitutive cytokine in epidermal keratinocytes but is inducible.

Regulatory effects of 1alpha,25-dihydroxyvitamin D3 on inflammatory responses in psoriasis.

Topical application of 1alpha,25-dihydroxyvitamin D3 (VD3) is thought to be beneficial in psoriasis because of its action in regulating keratinocyte proliferation and inflammation mediated by various cytokines. We assessed the effect of VD3 on the production levels of interferon (IFN)-alpha, interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha in mitogen-stimulated peripheral blood mononuclear cells (PBMC) of psoriatic patients. The results demonstrated that VD3 significantly inhibited IFN- , IL-6, and IL-8 levels produced by concanavalin A (Con A)-stimulated PBMC of psoriatic patients in a dose-dependent manner, and reduced mRNA expression for IFN- and IL-8. These findings suggest that in addition to the direct anti-proliferation effect on keratinocytes, VD3 may down-regulate the inflammatory cytokine production by infiltrating cells in psoriatic lesions.

Suplatast tosilate (IPD), a new immunoregulator, is effective in vitiligo treatment.

The major type of vitiligo is considered to be an autoimmune disorder. Anti-melanocyte antibodies are frequently detected in sera of patients with this disease. Interleukin (IL)-4 released from Th2 cells is an important factor in stimulating autoantibody production by B-cells. In this study, seven patients with vitiligo treated with suplatast tosilate (IPD), three showed repigmentation and improvement of their lesions after administration of the drug. IPD halted the continuous spread of the lesions in three of the other patients, and, in two of them, also reduced microsome test and thyroid test titers. The efficacy of IPD in treating vitiligo was thought to be due to the suppressive effect of this drug on IL-4 production. No side effect was observed. Thus IPD may represent a new alternative in vitiligo treatment due to its inhibition of autoimmunity by the suppression of IL-4.

Streptococcal infection in the pathogenesis of Behçet's disease and clinical effects of minocycline on the disease symptoms.

Although the precise pathoetiology of Behçet's disease (BD) remains obscure, patients with BD have a high incidence of chronic infectious foci, indicating an enhanced susceptibility to chronic tonsillitis, and dental caries. Sometimes, clinical symptoms appear after treatment of these foci in BD patients. It is believed that BD might be related to an allergic reaction to a bacterial infection in view of the many clinical symptoms, especially the presence of aphthous and genital ulcerations. An attempt to obtain cutaneous responses to bacterial antigens has been carried out using various vaccines developed from bacteria isolated from the ulcerative lesions and oral cavities of BD patients. BD patients often show intense hypersensitivity to various strains of streptococci, not only by their cutaneous reactions but also by in vitro testing. In this report, we describe our previous studies on the correlation between streptococcal antigens and the pathogenesis of BD and also discuss the recent reports of other authors. The intense hypersensitivity to streptococcal antigens acquired after streptococcal infection is thought to play an important role in the appearance of symptoms in BD patients since the production of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMC) was enhanced when stimulated with streptococcal antigen in a culture system. Minocycline, an antibiotic to which certain strains of streptococci are sensitive, reduced the frequency of clinical symptoms in BD patients as well as the production of pro-inflammatory cytokines by BD-PBMC stimulated with streptococcal antigen.