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Staphylococcal exotoxins stimulate nitric oxide-dependent murine macrophage tumoricidal activity
D J Fast1, B J Shannon, M J Herriott
1Biomedical Division, Samuel Roberts Noble Foundation, Inc., Ardmore, Oklahoma 73402.
Abstract:
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.
Insights
Staphylococcal exotoxins, toxic shock syndrome toxin 1 (TSST-1) and enterotoxin B, activate murine macrophages to kill tumor cells. This tumoricidal activity relies on nitric oxide production, not reactive oxygen intermediates.
Area of Science:
- Immunology
- Microbiology
- Toxicology
Background:
- Staphylococcal exotoxins are potent bacterial toxins.
- Macrophage activation is crucial for anti-tumor immunity.
Purpose of the Study:
- To investigate the tumoricidal activity of staphylococcal exotoxins.
- To elucidate the mechanisms underlying toxin-induced macrophage activation.
Main Methods:
- Murine peritoneal macrophages (PM) were stimulated with TSST-1 and enterotoxin B.
- Tumoricidal activity was assessed against P815 tumor targets.
- Nitric oxide (NO) and reactive oxygen intermediate (ROI) production were measured.
Main Results:
- Both TSST-1 and enterotoxin B induced tumoricidal activity in gamma interferon-primed PM.
- Toxin-stimulated tumoricidal activity was dependent on nitric oxide production.
- TSST-1 induced tumor necrosis factor secretion.
- Toxin-induced tumoricidal activity was independent of reactive oxygen intermediates.
Conclusions:
- Staphylococcal exotoxins stimulate macrophages to produce nitric oxide for tumor cell killing.
- Nitric oxide may play a role in the pathogenesis of staphylococcal infections.