Modulation of Phagocytosis by Tumor Promoters and Epidermal Growth Factor in Normal and Transformed Macrophages

The effects of the potent tumor promoter, 12-O-tetradeca-noylphorbol-13-acetate (TPA), on the phagocytosis of opsonized and unopsonized chromated sheep red blood cells (SRBC] by thioglycollate and divinyl ether maleic anhydride copolymer-recruited mouse peritoneal macrophages, and the transformed macrophage-like cell line, P388Di, were studied. With thioglycollate and divinyl ether maleic anhydride copolymen macrophages, phagocytosis of opsonized SRBC was inhibitec 50 to 60% by concentrations of TPA in the range of 17 on while lower concentrations in the range of 0.017 nM producec a 20 to 30% stimulation of phagocytosis. With the P388Di cell line, a dose-related stimulation of phagocytosis up to 80% above control was observed with TPA in the range of 0.017 to 17 nM. In all three cell types, phagocytosis of unopsonized SRBC was stimulated by TPA reaching a maximum of 40 to 75% above controls in the range of 17 nM. With a series of macrocyclic diterpenes related to TPA, a correlation was found between their ability to modulate phagocytosis in each of the cell types and their potencies as promoters in mouse skin carcinogenesis. Epidermal growth factor, which shares several effects with TPA, at 0.16 to 16 nM stimulated phagocytosis of unopsonized SRBC by 20 to 60% in all three types of macrophages. On the other hand, with opsonized SRBC, although epidermal growth factor stimulated phagocytosis in P388Di cells up to 60% above controls at 1.6 nM, it had no effect on thioglycollate or divinyl ether maleic anhydride copolymer macrophages. The responses produced by TPA and epidermal growth factor were due to a direct effect on the macrophages and not to an opsonic effect on the SRBC. These results provide additional evidence that tumor promoters exert highly pleiotropic effects on cell surface and membrane functions.