title: Cellular and cytokine dependent monocyte-mediated leukemic cell death: modulation by interferon-gamma and tumor necrosis factor-alpha.
abstract: Activated human monocytes and macrophages are involved in host defense against neoplastic cells. In view of cellular adoptive immunotherapy, we have studied the role of tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (IFN-gamma) in monocyte-mediated cytotoxicity on the level of both effector and leukemic target cells. Highly purified and IFN-gamma-activated monocytes were cytolytic to U937 cells up to 81.9 +/- 5.3% (mean +/- SEM) in a 24-hour MTT cytotoxicity assay at an effector-to-target-cell ratio of 10. Upon IFN-gamma activation these monocytes showed a 20-fold increase in TNF-alpha secretion of 663 +/- 122 pg/mL. Comparable concentrations of recombinant human TNF-alpha showed only cytostatic effects on U937 cells of approximately 20% after 24 hours, similar to the cytostatic effects of IFN-gamma-activated monocyte culture supernatants. These effects could be fully reversed by anti-TNF-alpha antibodies. U937 cells pretreated with TNF-alpha were almost completely resistant to monocyte-mediated cytotoxicity, supernatant-mediated cytostasis and to TNF-alpha up to 10(4) U/mL. IFN-gamma-activated monocytes were able to lyse TNF-alpha-modified U937 cells whereas IFN-gamma-activated monocyte supernatants showed only cytostatic activity after prolonged incubation. Additionally, target cell modulation by IFN-gamma potentiated the TNF-alpha-dependent cytolytic and cytostatic effects of monocytes, monocyte culture supernatants and TNF-alpha. We conclude that monocytes as a cellular component in monocyte-mediated cytotoxicity are far more potent in lysis of leukemic target cells than are secreted monokines. Furthermore, IFN-gamma and TNF-alpha are involved in the regulation of the susceptibility of leukemic cells for lysis by interactions with monocytes.
authors.affiliation: Department of Hematology, University Hospital, Amsterdam, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: van de Loosdrecht
authors.forename: R H
authors.initials: RH
authors.lastname: Beelen
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: M G
authors.initials: MG
authors.lastname: Broekhoven
authors.forename: M M
authors.initials: MM
authors.lastname: Langenhuijsen
mesh_terms: D000906:Antibodies / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D003124:Colorimetry; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology* / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma