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

Abstract

The trimeric high-affinity IgE receptor (FcεRI) on human epidermal Langerhans cells mediates IgE-dependent antigen uptake and subsequent antigen focusing. Its expression is upregulated on Langerhans cells (FcεRIhigh Langerhans cells) and inflammatory dendritic epidermal cells (FcεRIhigh inflammatory dendritic epidermal cells) in the skin of patients with atopic dermatitis. In the absence of the amplifying β-chain in these cells, FcεRI signaling (indicated by calcium mobilization and activation of the transcription factor nuclear factor-κB) is only detectable in FcεRIhigh Langerhans cells from atopics, but not FcεRIlow Langerhans cells from nonatopics. Therefore we investigated protein-tyrosine kinases putatively involved in FcεRI signaling in Langerhans cells and asked whether differences in their expression and FcεRI-induced activity could explain the dichotomic responses observed in atopic vs nonatopic individuals. First, we found the src protein-tyrosine kinases p53/56lyn, p59fyn, p56/59hck, p55c-fgr, and p60c-src to be expressed in Langerhans cells from all donors. In addition, whereas p56lck was lacking, p72syk and the negative regulatory p50csk were detected. Upon terminal maturation of Langerhans cells in vitro, no significant change of the protein- tyrosine kinase expression profile except downregulation of p56/59hck was observed. In contrast, significant upregulation of all protein-tyrosine kinase expressed except p50csk was detected in FcεRIhigh Langerhans cells, but not in FcεRIhigh 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 FcεRI triggering in FcεRIhigh Langerhans cells from atopics, but not in FcεRIlow Langerhans cells from nonatopics. Therefore, upregulation of FcεRI 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 FcεRIhigh Langerhans cells from atopic individuals