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Exogenous Administration of Gangliosides Inhibits FcRI-Mediated Mast Cell Degranulation by Decreasing the Activity of Phospholipase C¹

Lubica Dráberová^*, Lenka Dudková, Michael Boubelík^*, Helena Tolarová^*, Frantiek míd and Petr Dráber^2,*

^* Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic; and Institute of Clinical Biochemistry and Laboratory Diagnostics, 1st Medical Faculty, Charles University, Prague, Czech Republic

Gangliosides released from tumor cells, as well as administered exogenously, suppress the immune responses by largely unknown mechanisms. We show here that a pretreatment of rat basophilic leukemia cells with isolated brain gangliosides inhibited the release of preformed secretory mediators from cells activated via FcRI but not Thy-1 glycoprotein. Exogenously administered gangliosides also affected the cell-substrate adhesion and the levels of polymeric filamentous actin in Ag-activated cells. Although the production of phosphoinositides was also decreased, enzymatic activity of phosphatidylinositol 3-kinase was not inhibited. Gangliosides had no or only marginal effect on the association of aggregated FcRI with glycosphingolipid-enriched membranes and on tyrosine phosphorylation of FcRI and the linker for activation of T cells. Though pretreatment with gangliosides did not inhibit the association of linker for activation of T cells with phospholipase C (PLC)1 and PLC2, tyrosine phosphorylation of these enzymes, as well as their enzymatic activities and association with detergent-insoluble signaling assemblies were reduced. This resulted in a decreased production of inositol 1,4,5-trisphosphate and an inhibition of Ca²⁺ mobilization. The combined data support the concept that exogenously administered gangliosides interfere with those properties of glycosphingolipid-enriched membranes that are important for the formation of plasma membrane-associated signaling assemblies containing PLC but not for initial tyrosine phosphorylation of FcRI subunits.

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