Molecular consequences of human mast cell activation following immunoglobulin E-high-affinity immunoglobulin E receptor (IgE-Fc epsilon RI) interaction

The cross-linking by immunoglobulin E of its high-affinity receptor, Fc eps ilon RI, on mast cells initiates a complex series of biochemical events lea ding to degranulation and the synthesis and secretion of eicosanoids and cy tokines through the action of transcription factors, such as nuclear factor -kappa B. The initial activation involves the phosphorylation of Fc epsilon RI beta- and gamma-subunits through the actions of the tyrosine kinases ly n and syk. For the purposes of description, the subsequent events may be gr ouped in three cascades characterized by the key proteins involved. First, the phospholipase C-inositol phosphate cascade activates protein kinase C a nd is largely responsible for calcium mobilization and influx. Second, acti vation of Ras and Raf via mitogen-activated protein kinase causes the produ ction of arachidonic acid metabolites. Third, the generation of sphingosine and sphingosine-1-phosphate occurs through activation of sphingomyelinase. While the early signaling events tend to be specific for the cited cascade s, there is an increasing overlap of activated proteins with the downstream propagation of the signal. It is the balanced interaction between these pr oteins that culminates in degranulation, synthesis, and release of eicosano ids and cytokines. (C) 1999 Elsevier Science Inc.