The interaction between Lyn and Fcε RIβ is indispensable for Fcε RI-mediated human mast cell activation.

Background Fcε RIβ reportedly functions as an amplifier of the Fcε RIγ-mediated activation signal using a reconstitution system. However, the amplification mechanisms in human mast cells ( MCs) are poorly understood. We previously reported the hyperexpression of Fcε RIβ of MCs in giant papillae from vernal keratoconjunctivitis patients, compared with that in conjunctivae from nonallergic conjunctivitis patients. Elucidation of the molecular mechanisms of the amplification induced by Fcε RIβ should provide new targets for novel therapeutic interventions. The aim is to understand in greater details the function of Fcε RIβ in human MC Fcε RI expression and signaling. Methods Fcε RIβ and Lyn expression was reduced using a lentiviral sh RNA silencing technique. Localization of Lyn and Fcε RIβ in cultured MCs was examined by confocal microscopic analysis. Mediators were measured by ELISAs. Results The diminution of Fcε RIβ significantly downregulated cell surface Fcε RI expression and Fcε RI-mediated mediator release/production. The downregulation of Fcε RI-mediated degranulation was not only due to the decrease in Fcε RI expression. The diminution of Fcε RIβ inhibited the redistribution of Lyn within the cell membrane following Ig E sensitization. The diminution of Lyn in MCs significantly downregulated Fcε RI-mediated degranulation. The recombinant cell-penetrating forms of phosphorylated Fcε RIβ immunoreceptor tyrosine-based activation motif ( ITAM) for intracellular delivery disturbed the interaction between Lyn and phosphorylated endogenous Fcε RIβ ITAM, resulted in inhibiting Ig E-dependent histamine release from MCs in vitro and from giant papillae specimens ex vivo. Conclusion The interaction between Lyn and Fcε RIβ is indispensable for Fcε RI-mediated human MC activation, and specific inhibition of the interaction may represent a new therapeutic strategy for the treatment of human allergic diseases. [ABSTRACT FROM AUTHOR]