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Department of Surgery, Division of Surgical Research, Rhode Island Hospital, and Brown University School of Medicine, Providence, Rhode Island 02903
Work reported here investigated aspects of macrophage-mediated tumor cell death, in particular the role of apoptosis as a mechanism for nitric oxide (NO)-mediated macrophage tumor cytotoxicity. Nitric oxide induced apoptosis in P815 cells in macrophage P815 cocultures where fragmentation of tumor cell [3H]thymidine-labeled DNA preceded cell lysis (as measured by 51Cr release), paralleled nitrite accumulation, and was prevented by a specific inhibitor of NO synthase, N-MMA. DNA from P815 cells separated from macrophages in culture by a cell-impermeable membrane or exposed to authentic NO gas showed the pattern of internucleosomal cleavage that is characteristic of apoptosis. Additionally, culture of P815 cells with the NO donor sodium nitroprusside was followed by DNA fragmentation. Macrophages also induced apoptosis in L929 cells but, in this case, apoptosis was NO independent and partially inhibited in cocultures by an antitumor necrosis factor 
monoclonal antibody. The anti-tumor necrosis factor monoclonal antibody fully prevented apoptosis when macrophages and L929 were separated by a cell-impermeable membrane. Exposure of L929 cells to NO gas or sodium nitroprusside did not result in their apoptotic death. Like other immune cytotoxic cells, macrophages can determine tumor cell death through the induction of apoptosis and do so through more than one effector mechanism.
1 This work was supported by NIH Grant GM-42859, the Anita Allard Memorial Fund, and by funds allocated to the Department of Surgery by Rhode Island Hospital.
2 To whom requests for reprints should be addressed, at Department of Surgery, Division of Surgical Research, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903.
Received 10/22/93. Accepted 2/23/94.
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