Stimulation of phosphatidylinositol turnover is a key event for Fas-dependent, activation-induced apoptosis in human T lymphocytes.
We have analyzed the requirements for activation-induced apoptosis in Jurkat T cells expressing the heterologous human muscarinic type 1 receptor (HM1R; J-HM1-2.2 cells) that is coupled to phosphatidylinositol turnover through a protein tyrosine kinase-independent, G protein-regulated mechanism. Triggering of HM1R with the agonist carbachol is sufficient to induce apoptosis in J-HM1-2.2 cells. Apoptosis is also induced in J-HM1-2.2 cells by triggering of the TCR. Calcium influx, intracellular Ca2+ increase, calcineurin function, and de novo protein synthesis are necessary for receptor-controlled apoptosis. However, blocking protein kinase C with a specific inhibitor does not abrogate receptor-induced apoptosis. Furthermore, HM1R-induced apoptosis is inhibited by blocking Fas ligand/Fas interaction with an antagonist anti-Fas Ab, and Fas ligand mRNA and protein are expressed in J-HM1-2.2 cells stimulated through the HM1R. Therefore, protein tyrosine kinase activation is not an absolute requirement for receptor-controlled Fas ligand expression. Taken together, the results demonstrate that stimulation of phosphatidylinositol turnover can induce apoptosis through a Fas-dependent mechanism that requires calcineurin stimulation, but not protein kinase C activation.
Izquierdo
M
M
Institute of Parasitology and Biomedicine, Granada, Spain.
Ruiz-Ruiz
M C
MC
López-Rivas
A
A
D017209:Apoptosis / Q000276:immunology*; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell; D008562:Membrane Glycoproteins / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism* / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
D002148:Calmodulin-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D011493:Protein Kinase C; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium