The staphylococcal exotoxins toxic shock syndrome toxin 1 (TSST-1) and enterotoxin B were tested for their ability to stimulate murine peritoneal macrophages (PM) for tumoricidal activity. Both toxins were found to stimulate oil-elicited, gamma interferon-primed PM monolayers to kill nonadherent P815 tumor targets. The mechanism of killing of toxin-stimulated tumoricidal activity involved the production of nitric oxide, as nitrite could be demonstrated in culture fluids, and NG-monomethyl-L-arginine, an inhibitor of nitric oxide production, abrogated toxin-stimulated tumoricidal activity. TSST-1 stimulated the secretion of tumor necrosis factor by PM monolayers in the presence and absence of gamma interferon. The mechanism of toxin-stimulated tumoricidal activity was also determined to be independent of the production of reactive oxygen intermediates in that TSST-1 failed to stimulate H2O2 production by PM. These results demonstrate that the staphylococcal exotoxins are capable of stimulating macrophage production of nitric oxide for tumor cytotoxicity and suggest that the nitric oxide thus produced may subsequently play a role in the pathogenesis of the diseases caused by these toxins
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