MAST-CELL GRANULES INHIBIT MACROPHAGE-MEDIATED LYSIS OF MASTOCYTOMA-CELLS (P815) AND NITRIC-OXIDE PRODUCTION

The effects of mast cell granules (MCGs) on macrophage-mediated lysis of P815 mastocytoma cells and nitric oxide (NO) production were studie d. Murine peritoneal macrophages exhibited tumor cell killing and NO p roduction only when activated with lipopolysaccharide (LPS) or interfe ron-gamma (IFN-gamma). Coincubation of macrophages with MCGs during LP S activation dose-dependently inhibited macrophage-mediated tumor cell lysis. The MCG effect was not due to inactivation or removal of LPS b y MCG. The inhibitory effect was also not due to histamine or serotoni n present in the MCGs. The granules were not toxic to macrophages or P 815 mastocytoma cells. The effect of MCGs on macrophage-mediated tumor cell killing was evident whether MCGs were added before or after a 4- h exposure of macrophages to LPS. However, the inhibitory effect was n ot seen if MCGs were added after macrophages had been exposed to LPS f or 24 h. To assess whether MCGs could inhibit a non-LPS trigger, MCGs were tested on macrophages activated with IFN-gamma. In these experime nts, MCGs dose-dependently inhibited macrophage-mediated tumor cell ki lling induced by IFN-gamma, LPS, or IFN-gamma plus LPS. Furthermore, i n parallel experiments, MCGs significantly inhibited macrophage NO pro duction induced by LPS, IFN-gamma, or IFN-gamma plus LPS. Pretreatment of MCGs with diisopropylfluorophosphate, a serine protease inhibitor, only partially abrogated the effects of MCGs. The results demonstrate that MCGs inhibit both LPS- and IFN-gamma-induced macrophage killing of P815 cells and the inhibition is associated with the decrease of NO production.