IFN-γ is detected in chronic lesions of atopic dermatitis (AD); however, its specific role remains to be elucidated. An impaired stratum corneum barrier function is a hallmark of AD, and it is associated with a reduction in ceramides with long-chain fatty acids (FAs) in the stratum corneum. FA elongases, ELOVL1 and ELOVL4, are essential for the synthesis of these ceramides, together with ceramide synthase 3 (CerS3). We have previously shown that IFN-γ, but not other cytokines, induced the downregulation of these enzymes in cultured keratinocytes. Our aim was to investigate the in vivo role of IFN-γ in the lesional skin of AD by analyzing mouse dermatitis models. The local mRNA expression of IFN-γ increased in mite fecal antigen-induced AD-like dermatitis in NC/Nga mice but not in imiquimod-induced psoriasis-like dermatitis in BALB/c mice. The mRNA expression of ELOVL1 and ELOVL4 significantly decreased in AD-like dermatitis, whereas ELOVL1 increased in psoriasis-like dermatitis. The expression of CerS3 increased slightly in AD-like dermatitis, but it increased by 4.6-fold in psoriasis-like dermatitis. Consistently, the relative amount of ceramides with long-chain FAs decreased in AD-like dermatitis but not in psoriasis-like dermatitis. These results suggest that IFN-γ in the lesional skin may reduce ceramides with long-chain FAs by decreasing the expression of ELOVL. Thus, IFN-γ may contribute to the chronicity of AD by impairing barrier function.

Sphingosine kinase (SK), a key enzyme in sphingosine-1-phosphate (S1P) synthesis, is known to be overexpressed in various types of cancer cells. The effects of anticancer agents on SK1/S1P signaling have not yet been fully assessed in melanoma cells. In the present study, we investigated the effects of the combination of FTY720, an S1P receptor antagonist, and cisplatin, a DNA-damaging agent, on the induction of the death of human melanoma cells, as well as the molecular mechanisms involved. The viability of various human melanoma cell lines was examined following treatment with anticancer drugs. The cisplatin-resistant SK-Mel-28 and cisplatin-sensitive A375 cell lines were selected for this analysis. Protein expression and apoptotic rates were evaluated by western blot analysis following treatment with cisplatin and/or FTY720. Following treatment with a combination of FTY720 and cisplatin, cell viability significantly decreased and the expression of apoptosis-associated cleaved poly(ADP-ribose) polymerase (PARP) was significantly higher in comparison to treatment with cisplatin alone in the SK-Mel-28 cells. In addition, the combination of FTY720 and cisplatin reduced the protein expression of SK1 and the phosphorylation levels of phosphoinositide 3-kinase (PI3K), Akt and mTOR in the SK-Mel-28 cells; the expression of epidermal growth factor receptor (EGFR) was also markedly reduced. These findings suggest that FTY720 and cisplatin synergistically induce cell death through the downregulation of the PI3K/Akt/mTOR pathway and the decrease in EGFR expression in SK-Mel-28 cells. Thus, the combination of FTY720 and cisplatin may have therapeutic potential for chemotherapy-resistant melanoma, and the effects are likely exerted through the downregulation of S1P signaling.

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Epidermolysis bullosa acquisita (EBA) is an autoimmune mechanobullous disease that is clinically characterised by blisters and erosions on the skin and mucous membranes (1). Patients with EBA exhibit autoantibodies to type VII collagen (2) and are usually treated with corticosteroids, immunosuppressive agents, colchicine, diaphenylsulfone (DDS), or intravenous immunoglobulin (IVIG); however, to our knowledge, minocycline has not been reported to be effective in such cases. In the present report, we describe a patient with EBA who was initially treated with corticosteroids, and then successfully treated with minocycline for recurrence of EBA following corticosteroid dose reduction. The histological examination of the skin eruptions indicated subepidermal bulla formation as well as infiltration of lymphocytes, eosinophils and neutrophils in the upper dermis. As minocycline is known to inhibit neutrophil and eosinophil recruitment as well as cytokine production, it may be considered as a therapeutic option for EBA, particularly in cases exhibiting infiltration within the skin lesion on histological examination. CASE REPORTA 71-year-old Japanese woman, weighing 44 kg, presented with a 1-month history of many bullae with slight itch on the skin over her entire body (Fig. 1a) and on the tongue (Fig. 1b) and oral mucosa. She had no history of allergy, and the laboratory data were within the normal ranges, including the leucocyte count (6,390/μl; normal range: 3,000-7,900/μl), eosinophil count (198/ μl; normal 100-500/μl) and IgG concetration (1,188 mg/dL; normal 890-1,850 mg/dL). Antinuclear antibodies were negative. Histological examination indicated subepidermal bulla formation along with infiltration of lym phocytes, eosinophils, and a small amount of neutrophils in the upper dermis ( Fig. 1c and d).Direct immunofluorescence (IF) examination of a biopsy specimen from erythema indicated the deposition of immunoglobulin (Ig) G and C3 at the basement membrane zone with u-serrated pattern (3). Indirect IF using 1 M NaCl-split normal human skin sections showed IgG anti-basement membrane zone antibodies, which reacted with the dermal side. Using an enzyme-linked immunosorbent assay (ELISA: MBL, Nagoya, Japan), the titres of IgG antibody to type VII collagen were 76.7 and 146.6, at the first consultation and 2 weeks after the first consultation, respectively (Fig. 2). Antibodies to desmo glein 1 and 3, bullous pemphigoid (BP) 180, and BP 230 were not detected in the patient's serum by ELISA. Based on the clinical features, histopathological findings, IgG deposition at the basement membrane zone, and presence of IgG antibodies to type VII collagen in serum, we diagnosed the patient with EBA. Although the patient was then treated with prednisolone (45 mg/day), the new development of bullae was still noted. The addition of cyclosporine (150 mg/day) to the regimen inhibited the formation of new bullae, and the prednisolone dose could be gradually reduced. However, during this dose reduction period, when the patient was being tr...

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