Potentiation of direct antitumor cytotoxicity and production of tumor cytolytic factors in human blood monocytes by human recombinant interferon-gamma and muramyl dipeptide derivatives.
We investigated whether human peripheral blood monocytes isolated by centrifugal elutriation from healthy donors could be activated to become tumoricidal and release tumor cytolytic factor (TCF) subsequent to incubation with recombinant human interferon-gamma (r-IFN-gamma) or a derivative of muramyl dipeptide (nor-MDP), or both. Blood monocytes incubated in endotoxin-free medium containing up to 1000 U/ml of r-IFN-gamma or in medium containing less than 1 microgram/ml of nor MDP were not activated to lyse radiolabeled allogeneic human tumor cells. In contrast, the incubation of monocytes with various dose combinations of r-IFN-gamma and nor-MDP generated significant direct cytotoxic activity as well as production of TCF. Preincubation of the r-IFN-gamma and nor-MDP mixture with polymyxin B did not inhibit the synergism, thus ruling out the possibility that the process was due to endotoxin contamination. TCF harvested from monocyte culture supernatants was cytolytic against five allogeneic tumor targets, but not against a nontumorigenic cell line. Collectively, the data demonstrate that r-IFN-gamma can prime human blood monocytes to allow their activation by synthetic nor-MDP.
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Lopez-Berestein
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Fidler
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D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects; D009000:Monocytes / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D011112:Polymyxin B / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha
D006023:Glycoproteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma; D011112:Polymyxin B