Immunoglobulins from Graves' disease patients stimulate phospholipase A(2) and C systems in FRTL-5 and human thyroid cells

We have studied the effects of immunoglobulin G from Graves' disease patients on phospholipase A(2) (PLA(2)) and C (PLC) systems in FRTL-5 and human thyroid cells. Immunoglobulin G (IgG) from Graves' disease patients stimulated arachidonic acid (AA) release in a time- and dose-dependent manner, In FRTL-5 thyroid cells, removal of external calcium had no significant effect on the IgG (20 mu g/ml)-induced AA release in FRTL-5 thyroid cells. U-73122 (3 mu mol/l), a PLC inhibitor, and quinacrine (100 mu mol/l) but not U-26384 (5 mu mol/l), PLA(2) inhibitors, blocked the IgG-induced (20 mu g/ml) AA release in FRTL-5 thyroid cells. Immunoglobulin G (100 mu g/ml) also stimulated accumulation of inositol-1,4,5-triphosphate (IP3) in a time- and dose-dependent (20-300 mu g/ml) manner in FRTL-5 cells. Immunoglobulin G from Graves' disease patients induced a significant increase of IP3 production (p=0.01) compared to IgG from normal subjects, Removal of external calcium had no significant effect on the IgG-induced IP3 production. The PLC inhibitor U-73122 completely blocked IgG-induced IP3 production from FRTL-5 thyroid cells. Also, in human thyroid cells, IgG from Graves' disease patients induced a significant increase of AA release (p=0.001) and IP3 production (p=0.004) compared to the IgG from normal subjects. These data indicate that IgG from Graves' disease patients induced PLA(2) activity that was PLC dependent, a pattern referred to as sequential activation. Our studies suggest that IgG from Graves' disease patients activates PLA(2) and PLC systems in FRTL-5 and human thyroid cells. These signal transduction pathways could be involved in the pathogenesis of Graves' disease and future studies are warranted to investigate this area.