Exogenous administration of gangliosides inhibits Fc epsilon RI-mediated mast cell degranulation by decreasing the activity of phospholipase C gamma.
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 FcepsilonRI 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 FcepsilonRI with glycosphingolipid-enriched membranes and on tyrosine phosphorylation of FcepsilonRI 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)gamma1 and PLCgamma2, 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 Ca(2+) 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 PLCgamma but not for initial tyrosine phosphorylation of FcepsilonRI subunits.
D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005732:Gangliosides / Q000494:pharmacology*; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D005732:Gangliosides; D006028:Glycosphingolipids; D007166:Immunosuppressive Agents; D017455:Receptors, IgE; D014443:Tyrosine; D010738:Type C Phospholipases; D051966:Phospholipase C gamma