Endocytic and Tumoricidal Heterogeneity of Rat Liver Macrophage Populations

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Abstract
The macrophage population of the liver has been reported to be heterogenous with respect to endocytic and lysosomal enzyme activity. Yet we demonstrate that all liver macrophages in the rat can be activated to a tumoricidal state by the i.v. injection of liposomal muramyl dipeptide (MDP). After isolation, liver macrophages were fractionated according to size into five subfractions by means of elutriation centrifugation. Tumoricidal activity of liver macrophages, activated in vivo, was determined by an in vitro radioactivity release assay using B16 melanoma and C26 adenocarcinoma cells, labeled with [methyl-3H]thymidine, as target cells. Endocytic activity of the subpopulations both in vitro and in vivo was determined using [3H]-labeled liposome preparations. Finally, the extent to which the subpopulations become cytotoxic as a result of in vitro uptake of muramyl dideptide-(MDP)-containing liposomes was studied employing the cytotoxicity assay described above. No significant differences in cytotoxicity between the macrophage subfractions were observed after i.v. injection of liposomal MDP, although endocytic uptake of liposomes per cell increased proportionally to cell size, both in vitro and in vivo. We found that in vitro uptake of MDP-containing liposomes by the subfractions produced the highest cytolytic activity in the small to intermediate-size macrophages. When taking into consideration the different extents of liposome uptake it can be concluded that the smaller liver macrophages are significantly more susceptible to activation than the larger. In vivo, low activation potential is balanced by high liposome uptake capacity thus allowing the whole macrophage population in the liver to become involved in the eradication of metastatic tumor growth.