Study of the dependence of human monocytes and macrophages antitumoral properties upon TNF-alpha expression or release.

This study compares the antitumoral properties of isolated circulating human blood monocytes (Mo) and of mature macrophages (MO) obtained by 7 days differentiation of Mo or isolated from alveolar washing. These cells were activated to cytotoxicity in the presence of recombinant human interferon-gamma (rHuIFN-gamma). This antitumoral effect was measured at a low (1/1) effector/target ratio without pretreatment of the tumor cells. Activated Mo released tumor necrosis factor-alpha (TNF-alpha) in the culture medium where their antitumoral activity could be totally neutralized by specific anti-rHuTNF-alpha antibodies. In contrast, blood monocytes derived macrophages differentiated and activated in vitro expressed TNF-alpha on their membrane where it could be labelled and partially neutralized by anti-rHuTNF-alpha antibodies. Direct effector/target contact was required for the activity of macrophages differentiated in culture or collected from the lung cavity of healthy subjects. When these macrophages were obtained from infected patients or subjected to LPS treatment, they directly released cytotoxic amounts of TNF in the extracellular fluid after activation with IFN-gamma. Monocytes act mainly by soluble mediators (TNF-alpha being a key factor), while differentiated macrophages in the absence of endotoxin act by close cell to cell contact involving the lytic action of membranous TNF-alpha as well as some release of soluble TNF-alpha. We also present evidences (based on the use of various protease inhibitors) that the role of proteases is much less crucial in the cytotoxic action of monocytes and macrophages.