title: Cytokine modulated cell-membrane bound tumour necrosis factor expression is associated with enhanced monocyte-mediated killing of human leukaemic targets.
abstract: Cytokines such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) activate monocytes both in vitro and in vivo. We therefore studied whether the anti-leukaemic activity of monocytes could be augmented by IL-3 alone or in combination with GM-CSF. Using normal human monocytes stimulated with IL-3, GM-CSF, LPS or combinations of growth factor and LPS, we studied their cytotoxic activity against leukaemic cell-lines and primary AML blasts. IL-3 like GM-CSF, augmented the expression and secretion of TNF but did not prime for further expression and secretion of TNF in response to LPS. Neither GM-CSF or IL-3 increased the expression or secretion of TNF receptor p55 (TNF-Rp55), although both agents increased expression of TNF receptor p75 (TNF-Rp75). Monocyte-mediated cytotoxicity (MMC) against K562 and U937 cell-lines was increased by both GM-CSF and IL-3 stimulation, and both cytokines primed monocytes for increased killing of K562 and KG-1 cell-lines as well as primary AML blasts in response to LPS. The mechanism of action of MMC was largely confirmed to be via surface-bound TNF, although other TNF-independent mechanisms must have been involved.
authors.affiliation: Department of Haematology, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, Whitechapel, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Williams
authors.forename: A C
authors.initials: AC
authors.lastname: Newland
authors.forename: S M
authors.initials: SM
authors.lastname: Kelsey
mesh_terms: D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007938:Leukemia / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D007377:Interleukin-3; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007770:L-Lactate Dehydrogenase