Differential sensitivity of tumor targets to liver macrophage-mediated cytotoxicity

Abstract

Liver macrophages activated in vivo with bacterially derived lipopolysaccharide (LPS) display enhanced chemotaxis, phagocytosis, and oxidative metabolism. To determine if LPS also activates these mononuclear phagocytes for tumor cell killing, we compared the cytotoxic activity of macrophages from livers of rats treated with LPS (5 mg/kg, i.v.) with resident Kupffer cells. We found that both macrophage cell types displayed cytotoxicity towards rat N1S1 hepatoma and RBL-1 basophilic leukemia cells. Cytotoxicity of resident and LPS-activated liver macrophages towards these targets increased with cocultivation time, was dependent on the effector:target cell ratio, and appeared to involve extracellular lysis. No direct correlation between macrophage activation and cytotoxicity was observed towards these targets. While liver macrophages from LPS treated rats were more cytotoxic towards N1S1 cells, resident Kupffer cells were more cytotoxic towards RBL-1 cells. In further studies, resident Kupffer cells were also found to display extracellular cytolytic activity towards mouse P815 mastocytoma cells. In contrast, LPS-activated liver macrophage-mediated killing of these targets involved phagocytosis of intact tumor cells, as evidenced by light and electron microscopy and by uptake of 51Cr-labeled cells. These results suggest that cytotoxicity mediated by liver macrophages depends on the type of macrophage and the nature of the tumor cell target. In addition, cytotoxicity towards tumor targets appears to involve at least two different mechanisms including extracellular cytolysis and phagocytosis.