Prostaglandin D2 induces the production of human beta-defensin-3 in human keratinocytes.
The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes and protects the skin from infections. This peptide induces the release of a lipid mediator, prostaglandin D(2) from dermal mast cells. Prostaglandin D(2) binds to cell-surface G protein-coupled receptors, D prostanoid receptor, and chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (CRTH2). Both receptors are detected on epidermal keratinocytes. It is reported that prostaglandin D(2) is involved in cutaneous allergy, however, its role in antimicrobial defense is unknown. We examined the in vitro effects of prostaglandin D(2) on hBD-3 production in normal human keratinocytes. Prostaglandin D(2) enhanced hBD-3 secretion and mRNA expression in human keratinocytes. Prostaglandin D(2)-induced hBD-3 production was suppressed by the CRTH2 antagonist ramatroban and by antisense oligonucleotides against c-Jun and c-Fos, components of a transcription factor, activator protein-1 (AP-1). Prostaglandin D(2) enhanced the transcriptional activity and DNA binding of AP-1, expression, phosphorylation, and DNA binding of c-Fos proteins in keratinocytes. Prostaglandin D(2)-induced hBD-3 production, AP-1 activity, and c-Fos expression and phosphorylation were suppressed by U0126, PP2, and pertussis toxin, which are inhibitors of mitogen-activated protein kinase kinase (MEK), src, and G(i) proteins, respectively. The phosphorylation of extracellular signal-regulated kinase (ERK), downstream kinase of MEK, was induced by prostaglandin D(2), and suppressed by ramatroban, pertussis toxin, PP2, and U0126. These results suggest that prostaglandin D(2) induces hBD-3 production in human keratinocytes by activating AP-1 through the expression and phosphorylation of c-Fos via the CRTH2/G(i)/src/MEK/ERK pathway. Prostaglandin D(2) may promote cutaneous antimicrobial activity via hBD-3.
Kanda
Naoko
N
Department of Dermatology, Teikyo University School of Medicine, 11-1, Kaga-2, Itabashi-Ku, Tokyo 173-8605, Japan. nmk@med.teikyo-u.ac.jp
Ishikawa
Takeko
T
Watanabe
Shinichi
S
D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D023083:beta-Defensins / Q000096:biosynthesis*; D019061:src-Family Kinases / Q000502:physiology
C422950:DEFB103A protein, human; D016760:Proto-Oncogene Proteins c-fos; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D018808:Transcription Factor AP-1; D023083:beta-Defensins; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor