Role of the FcepsilonRI beta-chain ITAM as a signal regulator for mast cell activation with monomeric IgE.
The beta-chain of the high-affinity receptor for IgE (FcepsilonRI) plays a crucial role for amplification of the intracellular signaling in mast cells upon FcepsilonRI cross-linking by IgE*antigen complexes (IgE*Ag). Some monomeric IgE as well as IgE*Ag stimulate FcepsilonRI-signaling pathways, leading to cell activation, whereas the biological functions of the beta-chain in the monomeric IgE-mediated mast cell signaling and responses are largely unknown. In the present study, FcepsilonRI is reconstituted with either wild-type beta-chain or mutated beta-chain immunoreceptor tyrosine-based activation motif (ITAM) employing retrovirus-mediated gene transfer into the FcepsilonRI beta-chain-/- mast cells. We demonstrated that the transfectants with mutated beta-chain ITAM stimulated with monomeric IgE sufficiently produce inflammatory cytokines, although degranulation, intracellular Ca(2+) mobilization and leukotriene C(4) 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 beta-chain ITAM mutant cells stimulated with monomeric IgE, suggesting that the beta-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 beta-chain ITAM in both chemical mediator release and cytokine production of mast cells upon monomeric IgE stimulation.
Nunomura
Satoshi
S
Division of Molecular Cell Immunology and Allergology, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8910, Japan.
Gon
Yasuhiro
Y
Yoshimaru
Tetsuro
T
Suzuki
Yoshihiro
Y
Nishimoto
Hajime
H
Kawakami
Toshiaki
T
Ra
Chisei
C
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D007073:Immunoglobulin E; D007139:Immunoglobulin epsilon-Chains / Q000276:immunology; D017997:Leukotriene C4 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000378:metabolism; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D016207:Cytokines; D007139:Immunoglobulin epsilon-Chains; D017455:Receptors, IgE; D017997:Leukotriene C4; D007073:Immunoglobulin E; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D001619:beta-N-Acetylhexosaminidases; D002118:Calcium