Cytokine modulated cell-membrane bound tumour necrosis factor expression is associated with enhanced monocyte-mediated killing of human leukaemic targets

Cytokines such as interleukin-3 (IL-3) and granulocyte-macrophage colony-st imulating 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 facto r and LPS, we studied their cytotoxic activity against leukaemic cell-lines and primary AML, blasts. IL-3 like GM-CSF, augmented the expression and se cretion of TNF but did not prime for further expression and secretion of TN F in response to LPS. Neither GM-CSF or IL-3 increased the expression or se cretion of TNF receptor p55 (TNF-Rp55), although both agents increased expr ession 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 sti mulation, 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 TN F, although other TNF-independent mechanisms must have been involved. (C) 2 000 Elsevier Science Ltd. All rights reserved.