title: Effect of nuclear factor kappaB inhibition on tumor cell sensitivity to natural killer-mediated cytolytic function.
abstract: Inhibition of the transcription factor NF-kappaB has been reported to increase cell sensitivity to TNF and some cytotoxic drugs. We investigated the effect of NK-kappaB inhibition on the susceptibility of tumor cells to freshly isolated, nonactivated, human NK cells and to a TCRgamma/delta T cell clone displaying an MHC-unrestricted "NK-like" lysis. Using electrophoretic mobility shift assay, we first demonstrated that NF-kappaB/DNA binding activity was induced in target cells following coculture with NK cells or TCRgamma/delta T cell clone. To investigate the effect of target cell NF-kappaB inhibition on NK-mediated lysis, we blocked NF-kappaB translocation by introducing a human cDNA coding for a mutated IkappaB-alpha. Interestingly, our results indicated that inhibition of NF-kappaB did not induce any increase in either granzyme-dependent non-MHC-restricted cytotoxicity mediated by fresh non-stimulated NK cells and by TCR gamma/delta T cell clone or in CD95-mediated lysis. These results emphasize that NF-kappaB expressed in target cells does not play a role in the molecular process related to the control of target cell susceptibility to NK-mediated lysis and suggest that the NF-kappaB pathway is not a general mechanism for controlling the cytotoxic response.
authors.affiliation: Institut Gustave Roussy, Unité 487 INSERM "Cytokines et Immunologie des Tumeurs Humaines", Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: M
authors.initials: M
authors.lastname: Ameyar
authors.forename: G
authors.initials: G
authors.lastname: Dorothée
authors.forename: M
authors.initials: M
authors.lastname: Bentires-Alj
authors.forename: M
authors.initials: M
authors.lastname: Dziembowska
authors.forename: S
authors.initials: S
authors.lastname: Delhalle
authors.forename: F
authors.initials: F
authors.lastname: Gay
authors.forename: R
authors.initials: R
authors.lastname: Stancou
authors.forename: V
authors.initials: V
authors.lastname: Bours
authors.forename: S
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha