Histamine Enhances the Production of Granulocyte-Macrophage Colony-Stimulating Factor via Protein Kinase Cα 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.