title: Histamine enhances the production of granulocyte-macrophage colony-stimulating factor via protein kinase Calpha and extracellular signal-regulated kinase in human keratinocytes.
abstract: The production of granulocyte-macrophage colony-stimulating factor (GM-CSF) in keratinocytes is related to the chronicity of atopic dermatitis. Mast cell-derived histamine contributes to the cross-talk between mast cells and keratinocytes. We examined the effects of histamine on GM-CSF production in human keratinocytes. Histamine increased GM-CSF secretion, mRNA stability and promoter activity. Activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) elements on the promoter were responsible for the activation by histamine. Histamine enhanced transcriptional activity and DNA binding of AP-1 and NF-kappaB. Histamine shifted AP-1 composition form c-Jun homodimers to c-Fos/c-Jun heterodimers, and transiently expressed c-Fos protein. Histamine rapidly induced the phosphorylation and degradation of inhibitory kappaB. Histamine induced membrane translocation of protein kinase Calpha. Histamine-induced GM-CSF production was completely abolished by H1 antagonist pyrilamine and conventional protein kinase C inhibitor Gö6976, and partially suppressed by PD98059 which inhibits the activation of extracellular signal-regulated kinase. Gö6976 and PD98059 suppressed histamine-induced c-Fos expression and AP-1 activation. Gö6976 and PD98059 suppressed histamine-induced enhancement of NF-kappaB transcriptional activity. Histamine-induced phosphorylation and degradation of inhibitory kappaB was suppressed by Gö6976, but not by PD98059. These results suggest that histamine may enhance GM-CSF production at transcriptional and posttranscriptional levels via H1 receptor, protein kinase Calpha and extracellular signal-regulated kinase.
authors.affiliation: Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan. nmk@med.teikyo-u.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D052002:NF-kappa B p50 Subunit; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D006632:Histamine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases