We have previously shown that the arrest or regression of mouse liver metastases formed by lacZ-transduced ESbL T lymphoma cells (ESbL-lacZ) is associated with the stimulation of nitric oxide (NO) production by liver endothelial cells in sis. Here we studied in vitro the NO-mediated cytotoxicity against ESbL-lacZ target cells using well-characterized bovine endothelial cells (BEG) as effector cells. It was found that the co-culture of BEC with human TNF-alpha caused an increase of NO synthesis which could be completely blocked by the treatment with inducible NO synthase (iNOS) inhibitor N-G-monomethyl-L-arginine (NMMA). Incubation of activated BEC with metastatic lymphoma cells led to the death of the latter cells as evidenced by staining with propidium iodide and FAGS analysis. This cytotoxicity was considerably reduced after pretreatment of BEC with NMMA. Cytotoxic effects were also demonstrated after incubation of tumor cells with NO donor glycerol trinitrate (GTN). Non-activated BEC were not able to produce NO and showed a substantially lower level of cytotoxicity. The anti-tumor cytotoxicity exerted by activated BEC includes the stimulation of apoptosis in metastatic lymphoma cells which is mediated to a large extent by NO. These data reveal a novel role of endothelial cells in the elimination of metastatic cells through the induction of programmed cell death.

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