D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells.

BACKGROUND: Dopamine transduces signals via five subtypes of G protein-coupled receptors. Among these subtypes, the D1 and D5 receptors belong to the D1-like group. Although dopamine is known to mediate immune responses, its involvement in cutaneous immunity remains unclear. OBJECTIVE: The aim of this study is to determine the role of dopamine and its D1-like receptors in cutaneous immune responses. METHODS: By using the D1-like receptor antagonist SCH 23390, we examined the role of D1-like receptors in murine models of Th1-type contact hypersensitivity and Th2-type atopic dermatitis in vivo, and in mast cells and Th2 cell differentiation in vitro. RESULTS: Administration of SCH 23390 did not affect Th1-type contact hypersensitivity but suppressed the immediate-type reaction (ITR) and the late phase reaction (LPR) in the atopic dermatitis model. In addition, SCH 23390-treated mice showed higher IFN-γ and lower IL-4 mRNA levels in the ear skin of challenged mice than did non-treated mice as analyzed by real-time RT PCR. Consistently, the passive cutaneous anaphylaxis reaction was significantly reduced in SCH 23390-treated mice. Moreover, dopamine enhanced mast cell degranulation and Th2 cell differentiation, and both activities were abrogated by SCH 23390. CONCLUSION: These findings suggest that the D1-like receptors mediate immediate and late phase skin reactions by promoting Th2 induction and mast cell degranulation.

Topical cholecystokinin depresses itch-associated scratching behavior in mice.

Cholecystokinin (CCK) serves as a gastrointestinal hormone and also functions as a neuropeptide in the central nervous system (CNS). CCK may be a downregulator in the CNS, as represented by its anti-opioid properties. The existence of CCK in the peripheral nervous system has also been reported. We investigated the suppressive effects of various CCKs on peripheral pruritus in mice. The clipped backs of ICR mice were painted with CCK synthetic peptides and injected intradermally with substance P (SP). The frequency of SP-induced scratching was reduced significantly by topical application of sulfated CCK8 (CCK8S) and CCK7 (CCK7S), but not by nonsulfated CCK8, CCK7, or CCK6. Dermal injection of CCK8S also suppressed the scratching frequency, suggesting that dermal cells as well as epidermal keratinocytes (KCs) are the targets of CCKs. As determined using real-time PCR, mRNA for CCK2R, one of the two types of CCK receptors, was expressed highly in mouse fetal skin-derived mast cells (FSMCs) and moderately in ICR mouse KCs. CCK8S decreased in vitro compound 48/80-promoted degranulation of FSMCs with a transient elevation of the intracellular calcium concentration. These findings suggest that CCK may exert an antipruritic effect via mast cells and that topical CCK may be clinically useful for pruritic skin disorders.

Type of skin eruption is an independent prognostic indicator for adult T-cell leukemia/lymphoma.

Cutaneous involvement is seen in ~ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1.

Modulation of semaphorin 3A expression by calcium concentration and histamine in human keratinocytes and fibroblasts.

BACKGROUND: Both neurotrophins and chemorepellents are involved in the elongation and sprouting of itch-associated C-fibers in the skin. Nerve growth factor (NGF) and semaphorin 3A (Sema3A) are representatives of these two types of axon-guidance factors, respectively. OBJECTIVE: We investigated the effects of calcium concentration and histamine on the expression of NGF and Sema3A in normal human epidermal keratinocytes (NHEK) and normal human fibroblasts (NHFb). METHODS: NHEK and NHFb were cultured under different calcium concentrations (0.15-0.9 mM) with or without histamine, and the expression of mRNA for NGF and SEMA3A was assessed by real-time PCR analysis. An immunohistochemical study was performed for Sema3A using normal skin and skin cancer specimens. RESULTS: In NHEK, SEMA3A expression was elevated by high calcium concentration and reduced by low calcium condition, while NGF expression was not dependent on calcium. Their expressions were unchanged by calcium in NHFb. Immunohistochemically, keratinocytes in the prickle layer of normal epidermis and squamous cell carcinoma cells were positive for Sema3A, sparing basal cells and suprabasal cells. The addition of histamine to NHEK at 10 µg/ml enhanced SEMA3A expression but depressed NGF expression. In NHFb, however, histamine decreased both NGF and SEMA3A levels. CONCLUSIONS: Sema3A inhibits C-fiber elongation/sprouting in the upper layers of the epidermis, where calcium concentration is high, thereby determining the nerve endings. Histamine reduces Sema3A production by fibroblasts, allowing C-fibers to elongate in the dermis. In contrast, the histamine-augmented keratinocyte production of Sema3A might suppress C-fiber elongation and exaggerated pruritus.

Acute onset disseminated superficial porokeratosis associated with exacerbation of diabetes mellitus due to development of anti-insulin antibodies.

The development of disseminated superficial porokeratosis is occasionally observed in association with renal transplant, autoimmune diseases and various hematological disorders, suggesting a certain immunosuppression may trigger a widespread abnormal keratinization. Here we report a case of sudden onset disseminated superficial porokeratosis associated with an exacerbation of diabetes mellitus due to an anti-insulin antibody formation. To our knowledge, this is the first report of disseminated superficial porokeratosis in a patient with severe diabetes mellitus.

Therapeutic effectiveness of various treatments for eosinophilic pustular folliculitis.

Eosinophilic pustular folliculitis is a rare dermatosis. Recently, in addition to oral indomethacin, other treatments have been applied for eosinophilic pustular folliculitis. The aim of this study was to assess the effectiveness of various therapies encompassing conventional to newly applied drugs for eosinophilic pustular folliculitis. Twenty patients with eosinophilic pustular folliculitis seen in our department were investigated. The effectiveness of each treatment was assessed by a severity score index. Eleven patients were treated with oral indomethacin, and the severity scores of all patients were decreased after the treatment. Oral cyclosporine was markedly effective in all 11 patients treated, and topical tacrolimus ointment alleviated eosinophilic pustular folliculitis in 3 of 7 with one patient showing a remarkable reduction in the severity score. In addition to indomethacin or other oral non-steroidal anti-inflammatory drugs, oral cyclosporine and topical tacrolimus may be beneficial choices when patients have been resistant to previous treatments.

Aberrant aquaporin 5 expression in the sweat gland in aquagenic wrinkling of the palms.

Aquagenic wrinkling of the palms (AWP) is an uncommon disease characterized by the rapid and transient formation of edematous whitish plaques on the palms on exposure to water. Although this disease is occasionally accompanied by hyperhidrosis, the pathophysiology of AWP remains unknown. Herein we describe a patient with AWP. The location of wrinkling was limited to the areas positive for iodine-starch test after water exposure, which suggests that AWP is etiologically related to hyperhidrosis. Histologic examination revealed hyperplastic and papillated eccrine glandular epithelium with the enlarged diameter of eccrine coils. Immunohistochemically, while aquaporin 5 (AQP5), one of the water channel AQP families, was present exclusively in the dark cells of sweat glands of healthy donors, an aberrant AQP5 staining, extending to the clear cells, was found in the patient with AWP. The hyperplastic glandular epithelium and aberrant AQP5 staining in the patient's sweat glands suggest that AWP stems from dysregulation of sweating.