title: Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells.
abstract: Natural killer cells mediate spontaneously secretory/necrotic killing against rare leukemia cell lines and a nonsecretory/apoptotic killing against a large variety of tumor cell lines. The molecules involved in nonsecretory/apoptotic killing are largely undefined. In the present study, freshly isolated, nonactivated, human NK cells were shown to express TNF, lymphotoxin (LT)-alpha, LT-beta, Fas ligand (L), CD27L, CD30L, OX40L, 4-1BBL, and TNF-related apoptosis-inducing ligand (TRAIL), but not CD40L or nerve growth factor. Complementary receptors were demonstrated to be expressed on the cell surface of solid tumor cell lines susceptible to apoptotic killing mediated by NK cells. Individually applied, antagonists of TNF, LT-alpha1beta2, or FasL fully inhibited NK cell-mediated apoptotic killing of tumor cells. On the other hand, recombinant TNF, LT-alpha1beta2, or FasL applied individually or as pairs were not cytotoxic. In contrast, a mixture of the three ligands mediated significant apoptosis in tumor cells. These findings demonstrate that human NK cells constitutively express several of the TNF family ligands and induce apoptosis in tumor cells by simultaneous engagement of at least three of these cytotoxic molecules.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, PA 15213, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kashii
authors.forename: R
authors.initials: R
authors.lastname: Giorda
authors.forename: R B
authors.initials: RB
authors.lastname: Herberman
authors.forename: T L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: N L
authors.initials: NL
authors.lastname: Vujanovic
mesh_terms: D015703:Antigens, CD; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D053282:CD27 Ligand; D053285:CD30 Ligand; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D053308:Lymphotoxin-beta; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D053282:CD27 Ligand; D053285:CD30 Ligand; C505771:CD70 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505886:LTB protein, human; D008024:Ligands; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505774:TNFSF8 protein, human; D014409:Tumor Necrosis Factor-alpha