Role of the FcεRI β-chain ITAM as a signal regulator for mast cell activation with monomeric IgE

Abstract

The β-chain of the high-affinity receptor for IgE (FcεRI) plays a crucial role for amplification of the intracellular signaling in mast cells upon FcεRI cross-linking by IgE•antigen complexes (IgE•Ag). Some monomeric IgE as well as IgE•Ag stimulate FcεRI-signaling pathways, leading to cell activation, whereas the biological functions of the β-chain in the monomeric IgE-mediated mast cell signaling and responses are largely unknown. In the present study, FcεRI is reconstituted with either wild-type β-chain or mutated β-chain immunoreceptor tyrosine-based activation motif (ITAM) employing retrovirus-mediated gene transfer into the FcεRI β-chain-/- mast cells. We demonstrated that the transfectants with mutated β-chain ITAM stimulated with monomeric IgE sufficiently produce inflammatory cytokines, although degranulation, intracellular Ca2+ mobilization and leukotriene C4 synthesis are significantly reduced. Furthermore, analyses of molecular mechanisms of the signaling revealed that the expression of cytokine genes and activation of extracellular signal-regulated kinase 1/2 and protein kinase C were significantly delayed in the β-chain ITAM mutant cells stimulated with monomeric IgE, suggesting that the β-chain ITAM regulates kinetics of gene transcriptions and signaling pathways for cytokine production. These findings for the first time revealed the unique functions of the β-chain ITAM in both chemical mediator release and cytokine production of mast cells upon monomeric IgE stimulation. © The Japanese Society for Immunology 2005. All rights reserved.