Aggregation of the high-affinity IgE receptor FcεRI on human monocytes and dendritic cells induces NF-κB activation

Abstract

In contrast to mast cells and basophils, the high-affinity IgE receptor (FcεRI) on monocytes and dendritic cells (DC), including epidermal Langerhans cells, is not constitutively expressed and lacks the β-chain. FcεRI is upregulated on Langerhans cells of atopic individuals, particularly in atopic dermatitis skin. Although FcεRI provides IgE-mediated antigen focusing on monocytes and DC/Langerhans cells, its relevance for cell activation remains elusive, and the transcription factors regulating FcεRI-induced genes are unknown. We show that NF-κB, known to regulate genes essential for inflammatory responses and DC differentiation and function, is activated upon FcεRI ligation in primary human monocytes and DC. In Langerhans cells isolated from epidermis, NF-κB activation is restricted to donors expressing high FcεRI amounts. FcεRI-induced NF-κB complexes in monocytes and DC contain p50 and p65, but no other NF-κB subunits despite increased RelB expression during differentiation. NF-κB activation is preceded by serine phosphorylation and degradation of its inhibitory protein IκB-α without involving other IκB proteins. Finally, we show that FcεRI ligation on monocytes and DC leads to synthesis and release of tumor necrosis factor-α and monocyte chemoattractant protein-1, which is decreased by two mechanistically distinct inhibitors of NF-κB activation. Thus NF-κB activation represents a novel mechanism by which FcεRI on monocytes and DC potentially controls inflammatory reactions.