Fc Epsilon Ri Beta-Chain Itam Amplifies Pi3k-Signaling To Ensure Synergistic Degranulation Response Via Fc Epsilon Ri And Adenosine Receptors

Simultaneous stimulation with antigen and adenosine in mast cells induces a synergistic degranulation response at a low antigen dose that is insufficient to cause secretion by itself. This kind of stimulation is thought to be relevant to the immediate asthmatic response upon bronchial challenge with low-dose allergen. In this context, Fc epsilon RI- and adenosine receptor-mediated signalings cooperate to increase degranulation in mast cells. In the present study, we prepared mast cells that have mutations (Y219F/Y225F/Y229F) in three tyrosine residues of the Fc epsilon RI beta-chain (FcR beta)-ITAM in order to elucidate the molecular mechanisms of degranulation response synergistically elicited by costimulation with low-dose antigen and adenosine. Introduction of mutations in the FcR beta-ITAM abolished the synergistic degranulation response. Upon costimulation with low-dose antigen and adenosine, tyrosine phosphorylation of Grb2-associated binder 2, which is located upstream of PI3K-signaling, was significantly increased, but severely diminished in FcR beta-ITAM mutant cells. These findings indicate that FcR beta acts as a critical element in mast cell synergistic degranulation response through Fc epsilon RI and adenosine receptors, and that PI3K-signaling through FcR beta-ITAM is a crucial participant in augmentation of Fc epsilon RI-mediated degranulation by adenosine.