Abstract
The aggregation of high-affinity immunoglobulin E (IgE) receptors (FcεRI) on mast cells is a critical event in the initiation of an allergic reaction. Coengagement of FcεRI with immunoglobulin G (IgG) low-affinity receptor FcγRIIB/CD32 inhibits degranulation and the release of inflammatory mediators from mast cells and has therefore been proposed as a new therapeutic approach for the treatment of allergies. In this study, we investigated whether FcγRIIB, besides inhibiting degranulation, negatively regulates other signalling pathways downstream of FcεRI. For this, we determined the phosphorylation and/or expression of proteins involved in the regulation of mast-cell apoptosis. Coaggregation led to an attenuation of Akt phosphorylation but did not inhibit phosphorylation of transcription factor Foxo3a or its proapoptotic target, Bim. Similarly, FcεRI-dependent expression of the prosurvival gene A1 was not affected by coaggregation. Our data demonstrate that coengagement of FcεRI and FcγRIIB inhibits degranulation but not the signalling pathways regulating Bcl-2 family members Bim and A1.
Highlights
The aggregation of high-affinity immunoglobulin E (IgE) receptors (Fc⑀RI) on mast cells is a critical event in the initiation of an allergic reaction
The addition of TNP7-mouse anti-rabbit (MAR) F(ab)[2] will aggregate Fc⑀RI in cells sensitized with IgE, aggregate Fc␥RIIB in cells sensitized with 2.4G2 rat Ab, and coaggregate Fc⑀RI and Fc␥RIIB in cells sensitized with both IgE and 2.4G2 rat Ab
Since aggregation using 2.4G2 rat Ab together with TNP7-MAR F(ab)[2] does not cause degranulation, this indicates that expression of Fc␥RIII on C57 cells does not interfere with our system
Summary
The aggregation of high-affinity immunoglobulin E (IgE) receptors (Fc⑀RI) on mast cells is a critical event in the initiation of an allergic reaction. Binding of an allergen to IgE, already bound to its high-affinity receptor Fc⑀RI on mast cells, leads to aggregation and subsequent activation This initiates signalling events that typically result in degranulation, changes in gene expression, and the release of inflammatory mediators, contributing to acute and late-phase allergic. IgE-induced mast cell activation (ie, Fc⑀RI aggregation) is negatively regulated by coaggregation of Fc⑀RI with Fc␥RIIB.[9,12] The release of mediators and cytokines is inhibited in a process in which Fc⑀RI contributes to the ITIM-dependent inhibition of its own intracellular signalling This is achieved by the Fc⑀RI-associated tyrosine kinase Lyn, which phosphorylates the Fc␥RIIB ITIM that recruits SHIP1, leading to Fc⑀RI signal abrogation.[11,13,14] The receptors interact with the Factin skeleton that enables Fc␥RIIB to recruit SHIP1, which is provided by filamin-1. Investigations of the mechanism by which SHIP mediates its Fc␥RIIB inhibitory function have suggested p62dok as a possible mediator of Fc␥RIIB inhibition of Fc⑀RI signalling downstream of SHIP in mast cells.[16]
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