The role of mast cell specific gangliosides in modulating mediator release

Abstract

Mast cells are immunoregulatory cells that participate in various biological events such as host defense, angiogenesis, inflammatory and allergic reactions. These events are directly related to mast cell activation and subsequent mediator release. Mast cell activation generally occurs through the interaction of a multivalent antigen (allergen) with immunoglobulin E (IgE) bound to the high-affinity receptor for immunoglobulin E (Fc[RI) on the mast cell surface. Mast cells stimulation via Fc[RI also activates transcription factors NFAT and NFºB which results in the synthesis and release of cytokines. The early events in signal transduction occur in lipid rafts in plasma membrane. Immediately after FcµRI cross-linking, FcµRI and other signaling molecules are translocated into lipid rafts. Mast cell specific gangliosides derived from GD1b are also present in lipid rafts on the surface of the plasma membrane and are associated with FcµRI in activated mast cells. The cross-linking of these gangliosides by mAb AA4 promotes a partial activation of mast cells, similar to that observed by activation via FcµRI, but does not result in histamine release. Cross-linking the gangliosides derived from GD1b results in their capping on the cell surface. With time, the caps increase on the cell surface, which correlates with the inhibition of histamine release via Fc[RI. The present study aims to characterize the role of the gangliosides derived from GD1b in the signaling pathway in mast cells. The activation of NFAT and NFºB by cross-linking the gangliosides derived from GD1b will be investigated. It will also be determined if this activation is mediated by Syk (spleen tyrosine kinase). Whether or not the activation of these transcription factors also results in the release of neo-synthesized factors by mast cells will also be evaluated. Furthermore, the composition of lipid rafts will be characterized when the gangliosides derived from GD1b are aggregated or not. The knowledge of the role of gangliosides in mast cell signaling may lead to new therapeutic targets for allergic and inflammatory processes.