No abstract

Atopic dermatitis is characterized by increased skin innervation. The expression of neurotrophin-4 is enhanced in the epidermal keratinocytes of lesions with atopic dermatitis and may be related to hyperinnervation in these lesions. Prostaglandin E 2 (PGE 2 ) levels are increased in lesions with atopic dermatitis; thus, PGE 2 may be involved in the development of this disease. We examined the in vitro effects of PGE 2 on neurotrophin-4 production in human keratinocytes. PGE 2 and EP1/EP3 agonist sulprostone increased neurotrophin-4 secretion and mRNA levels without altering its mRNA stability. Antisense Sp1 oligodeoxynucleotide and Sp1 inhibitor mithramycin A suppressed PGE 2 and sulprostone-induced neurotrophin-4 expression, indicating the requirement for Sp1 for expression. PGE 2 or sulprostone markedly enhanced the phosphorylation, DNA binding, and transcriptional activity of Sp1 and modestly increased Sp1 mRNA and protein levels. PGE 2 or sulprostone induced the membrane translocation of protein kinase C␣ and the phosphorylation of extracellular signal-regulated kinase (ERK). PGE 2 -induced increases in neurotrophin-4 expression, Sp1 transcriptional and DNA-binding activity, Sp1 mRNA and protein levels, and ERK phosphorylation were suppressed by antisense EP3 oligodeoxynucleotide, inhibitors of phosphatidylinositol-specific phospholipase C, conventional protein kinase C, and mitogen-activated protein kinase/ERK kinase 1 (MEK1). These results suggest that PGE 2 enhances neurotrophin-4 production by activating Sp1 via the EP3/phosphatidylinositolspecific phospholipase C/protein kinase C␣/MEK1/ERK pathway. PGE 2 may promote innervation in skin lesions with atopic dermatitis via the induction of neurotrophin-4.

Triple extramammary Paget's disease, which consists ordinarily of bilateral axillary and genital lesions, is uncommon. Triple extramammary Paget's disease involving other sites has never been reported, although solitary extramammary Paget's disease can occur at various sites around the body. Erythematous plaques on the areola, axilla and genitalia of a 91-year-old man were surgically removed under the clinical diagnosis of multiple extramammary Paget's disease. Histology revealed that all three lesions consisted of intraepidermal nests of Paget cells and other isolated Paget cells scattered in the epidermis. Although adnexal invasion was observed in the genital lesion, neither intraductal invasion nor underlying breast carcinoma was detected in the areolar lesion. Immunohistochemically, the Paget cells in all lesions expressed simple epithelial cytokeratins (CK8, 18 and 19), mucin (MUC)1 and MUC5AC, but neither CK20 nor MUC2. From the histological findings, the present case was interpreted as triple extramammary Paget's disease rather than synchronous mammary and extramammary Paget's disease. Furthermore, the mucin core protein expression pattern, which was identical to that observed in extramammary Paget's disease, supported the above interpretation.