Prostaglandin E2 enhances neurotrophin-4 production via EP3 receptor in human keratinocytes.
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 Calpha 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/phosphatidylinositol-specific phospholipase C/protein kinase Calpha/MEK1/ERK pathway. PGE(2) may promote innervation in skin lesions with atopic dermatitis via the induction of neurotrophin-4.
Kanda
Naoko
N
Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan. nmk@med.teikyo-u.ac.jp
Koike
Satsuki
S
Watanabe
Shinichi
S
D015153:Blotting, Western; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014162:Transfection
D009414:Nerve Growth Factors; D016376:Oligonucleotides, Antisense; C545647:PTGER3 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016329:Sp1 Transcription Factor; C016767:sulprostone; D004247:DNA; D015232:Dinoprostone; C073922:neurotrophin 4