Contribution of inflammatory mast cell mediators to alterations in macrophage function after malathion administration

Recent studies using mast cell-deficient mice showed that the presence of mast cells was necessary for the increase in macrophage function observed after oral administration of malathion and reconstitution with bone marrow-derived mast cells restored the ability of malathion to increase macrophage function. In addition, the release of mast cell mediators (blocked by cromolyn) and histamine (action blocked by pyrilamine) was shown to be involved in the action of malathion on macrophage function. In the present study, the contribution of inflammatory mediators (i.e. arachidonic acid metabolites and tumor necrosis factor [TNF]) which may be generated by mast cells after oral administration of malathion, was examined. Controls in this study included the effect of the agent to be examined on: (1) resident peritoneal macrophages; and (2) macrophages elicited with pristane, an agent shown previously to stimulate macrophage function in the absence of mast cells. Intraperitoneal administration of indomethacin, an inhibitor of cycloxygenase, or neutralizing antibody to TNF 30 h before and 4 h after oral malathion blocked the ability of malathion to increase macrophage function, as measured by the generation of respiratory burst activity and the production of cathepsin D. On the other hand,administration of these agents to mice injected intraperitoneally with pristane did not affect the observed increase in cathepsin D production. Respiratory burst function after elicitation with pristane was slightly decreased (indomethacin) or not affected (antibody to TNF). The effect of intraperitoneal administration of nordihydroyaiaretic acid (NDGA), an inhibitor of both cycloxygenase and lipoxygenase, was also examined. Intraperitoneal administration of NDGA partially blocked the effects of oral administration of malathion on peritoneal macrophage function, but did not affect the function of resident or pristane-elicited peritoneal macrophages. These data suggest that inflammatory mediators (potentially released from mast cells upon stimulation) contribute to the elevation in macrophage function observed after oral malathion administration.