title: B-chronic lymphocytic leukemia cells exert an in vitro cytotoxicity mediated by tumor necrosis factor alpha.
abstract: Tumor necrosis factor alpha (TNFalpha) is constitutively produced by B-chronic lymphocytic leukemia (B-CLL) cells and may act as an autocrine factor for their growth and survival. However, very few data are available on the possible cytotoxic effect of TNFalpha produced by B-CLL cells. This study investigated whether B-CLL cells exert in vitro cytotoxicity by TNFalpha and if so, whether this cytotoxicity can be modulated by cytokines. In 8 of 12 patients (66.6%), B-CLL cells in vitro constitutively produced TNFalpha and exerted a TNFalpha-mediated cytotoxicity, evaluated in an 18-h 51Cr release assay, against the TNFalpha-sensitive Jurkat, U937 and K562 cell lines but not against the TNFalpha-resistant Raji cell line. Involvement of TNFalpha in B-CLL cell cytotoxicity is demonstrated by the fact that anti-TNFalpha antibodies strongly inhibited it and supernatants of cytotoxic cultures contained TNFalpha and mediated a completely TNFalpha-dependent cytotoxicity. When the cytotoxic B-CLL cells were stimulated with interleukin (IL)-2 plus IL-12, there was increased TNFalpha mRNA expression, TNFalpha production and TNFalpha-mediated cytotoxicity. All eight patients with cytotoxic leukemic cells had progressive disease and six of these also expressed high levels of ZAP-70 protein. In the other four patients (33.3%), B-CLL cells did not produce TNFalpha in vitro and were not cytotoxic, either spontaneously or after IL-2 plus IL-12 stimulation. Of these four patients, three had stable disease and one had progressive disease. The patient with progressive disease and one of the three with stable disease expressed low levels of ZAP-70 protein. We conclude that a group of B-CLL patients with progressive disease have leukemic B cells able to exert in vitro a TNFalpha-mediated cytotoxicity, which is modulated by cytokines.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Perugia, Via Brunamonti, General Hospital-Monteluce, 06122 Perugia, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rosati
authors.forename: Rita
authors.initials: R
authors.lastname: Sabatini
authors.forename: Antonio
authors.initials: A
authors.lastname: Tabilio
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
authors.forename: Andrea
authors.initials: A
authors.lastname: Bartoli
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Marconi
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000235:genetics; D051997:ADP-ribosyl Cyclase 1; D000368:Aged; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology*; D007958:Leukocyte Count; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D015703:Antigens, CD; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1