Differential regulation of the expression of CD95 ligand, receptor activator of nuclear factor-kappa B ligand (RANKL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-alpha during T cell activation.
Members of TNF superfamily are characterized by their ability to inflict apoptosis upon binding to their cognate receptors in a homotrimeric manner. These proteins are expressed on different cell types under various conditions. However, the mechanisms governing the expression of these molecules remain elusive. We have found that the TCR signal can elicit the expression of receptor activator of NF-kappaB ligand (RANKL), TNF-alpha, CD95L, and TNF-related apoptosis inducing ligand (TRAIL) in T cell hybridoma A1.1 cells, thus allowing us to examine the expression pattern of these molecules under precisely the same conditions. We have previously reported that CD95L expression requires both protein kinase C (PKC) translocation and Ca2+ mobilization and is inhibited by cyclosporin A, and dexamethasone. We demonstrate now that activation-induced expression of RANKL is mediated by Ca2+ mobilization. PKC activation does not induce RANKL expression nor does it synergize with the Ca2+ signal. Activation-induced RANKL expression is blocked by cyclosporin A, but not by dexamethasone. The expression of TNF, in contrast, is mediated by PKC, but not by Ca2+. TNF-alpha expression is not inhibited by cyclosporin A, but is sensitive to dexamethasone. A1.1 cells constitutively express TRAIL at low levels. Stimulation with anti-CD3 leads to an initial reduction and subsequent increase in TRAIL expression. TRAIL induction is not inhibited by cyclosporin A, but highly sensitive to dexamethasone. Therefore, expression of the TNF superfamily genes is regulated by distinct signals. Detailed understanding of the regulatory mechanisms could provide crucial information concerning the role of these molecules in the modulation of the immune system.
Wang
R
R
Department of Immunology and Tissue Biology, Jerome H. Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Zhang
L
L
Zhang
X
X
Moreno
J
J
Luo
X
X
Tondravi
M
M
Shi
Y
Y
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D020013:Calcium Signaling / Q000276:immunology; D002352:Carrier Proteins / Q000096:biosynthesis*; D006224:Cricetinae; D003513:Cycloheximide / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006825:Hybridomas; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D005810:Multigene Family / Q000276:immunology; D011493:Protein Kinase C / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505687:Tnfrsf11a protein, mouse; C505654:Tnfsf10 protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D003907:Dexamethasone; D003513:Cycloheximide; D011493:Protein Kinase C