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INFLAMMATION AND IMMUNOPHARMACOLOGY

Prostaglandin E₂ Enhances Neurotrophin-4 Production via EP3 Receptor in Human Keratinocytes

Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan

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 E₂ (PGE₂) levels are increased in lesions with atopic dermatitis; thus, PGE₂ may be involved in the development of this disease. We examined the in vitro effects of PGE₂ on neurotrophin-4 production in human keratinocytes. PGE₂ 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 PGE₂ and sulprostone-induced neurotrophin-4 expression, indicating the requirement for Sp1 for expression. PGE₂ or sulprostone markedly enhanced the phosphorylation, DNA binding, and transcriptional activity of Sp1 and modestly increased Sp1 mRNA and protein levels. PGE₂ or sulprostone induced the membrane translocation of protein kinase C and the phosphorylation of extracellular signal-regulated kinase (ERK). PGE₂-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 PGE₂ enhances neurotrophin-4 production by activating Sp1 via the EP3/phosphatidylinositol-specific phospholipase C/protein kinase C/MEK1/ERK pathway. PGE₂ may promote innervation in skin lesions with atopic dermatitis via the induction of neurotrophin-4.

Address correspondence to: Dr. Naoko Kanda, Department of Dermatology, Teikyo University, School of Medicine, 11-1, Kaga-2, Itabashi-Ku, Tokyo 173-8605, Japan. E-mail: nmk{at}med.teikyo-u.ac.jp

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