Enhanced Expression and Activity of Protein-tyrosine Kinases Establishes a Functional Signaling Pathway Only in FcεRIhigh Langerhans Cells from Atopic Individuals

The trimeric high-affinity IgE receptor (FceRI) on human epidermal Langerhans cells mediates IgE-dependent antigen uptake and subsequent antigen focusing. Its expression is upregulated on Langerhans cells (FceRI high Langerhans cells) and inflammatory dendritic epidermal cells (FceRI high inflammatory dendritic epidermal cells) in the skin of patients with atopic dermatitis. In the absence of the amplifying β-chain in these cells, FceRI signaling (indicated by calcium mobilization and activation of the transcription factor nuclear factor-κB) is only detectable in FceRI high Langerhans cells from atopics, but not FceRI low Langerhans cells from nonatopics. Therefore we investigated protein-tyrosine kinases putatively involved in FceRI signaling in Langerhans cells and asked whether differences in their expression and FceRI-induced activity could explain the dichotomic responses observed in atopic vs nonatopic individuals. First, we found the src protein-tyrosine kinases p53/56 lyn , p59 fyn , p56/59 hck , p55 c-fgr , and p60 c-src to be expressed in Langerhans cells from all donors. In addition, whereas p56 lck was lacking, p72 syk and the negative regulatory p50 csk were detected. Upon terminal maturation of Langerhans cells in vitro , no significant change of the protein- tyrosine kinase expression profile except downregulation of p56/59 hck was observed. In contrast, significant upregulation of all protein-tyrosine kinase expressed except p50 csk was detected in FceRI high Langerhans cells, but not in FceRI high inflammatory dendritic epidermal cells. Finally, the important protein-tyrosine kinases substrate phospholipase C-γ1, which is also essential for downstream calcium mobilization, was only phosphorylated upon FceRI triggering in FceRI high Langerhans cells from atopics, but not in FceRI low Langerhans cells from nonatopics. Therefore, upregulation of FceRI and protein-tyrosine kinase expression as well as subsequent protein-tyrosine kinase activity may explain, at least in part, that an efficient signaling pathway in terms of calcium mobilization is restricted to FceRI high Langerhans cells from atopic individuals.