This proposal is based on our recent discovery of new functions for human tumor necrosis factor (TNF) and new and unexpected relationships between TNF and interleukin-1 (IL-1) (Philip, R. and Epstein, L.B. Nature, in press, 1986). We found that TNF not only enhances the cytotoxicity of human monocytes for tumor cell targets but also mediates the enhanced monocyte cytotoxicity induced by IL-1, interferon (IFN)-gamma, and, in an autocrine manner, by TNF itself. We demonstrated that TNF and IL-1, both of which are monocyte products, also influence monocyte function and have the capacity to induce each other. Therefore, our overall objective in this proposal is to further our understanding of the comparative biology of TNF and IL-1 with emphasis on their ability to be produced by the effect human monocyte- macrophage function. Specifically, we shall determine 1) if recombinant IL-1-alpha and beta enhance monocyte cytotoxicity (as do natural IL-1 and recombinant TNF) and the kinetics of the response in short term 51Cr release assay; 2) whether TNF and IL- 1 are synergistic with each other or with interferon (IFN)-alpha or gamma in enhancing monocyte cytotoxicity; 3) whether TNF and IL-1-alpha or IL-1-beta compete for the same receptor on monocytes as assessed in binding studies using radiolabelled ligands; 4) whether TNF mediate the cytotoxicity of monocytes for human tumor targets as it does for murine targets; 5) the amount of TNF mRNA and protein produced by monocytes during their induction and cytotoxic phases after treatment with IL-1, IFN, or TNF itself; 6) which monocyte subsets produce and respond to TNF and IL-1 with enhanced cytotoxicity and whether they are the same for both TNF and IL-1; 7) whether tumor associated macrophages produce TNF and IL-1 and are capable of lysing autologous, allogeneic an xenogeneic tumor targets; 8) the ability of TNF or IL-1 alpha or IL-1 beta to increase the susceptibility of human tumor targets to monocyte cytotoxicity. Knowledge gained from this research should be of considerable importance to those who design and implement clinical trials with such agents as TNF and IL-1 or with other biological response modifiers and to investigators concerned with the basic biology of macrophage function.
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