NO IS NOT SUFFICIENT TO EXPLAIN MAXIMAL CYTOTOXICITY OF TUMORICIDAL MACROPHAGES AGAINST AN NO-SENSITIVE CELL-LINE

Nitric oxide (NO) is a macrophage cytotoxic effector, Results presente d here, however, demonstrate that NO does not fully explain macrophage cytotoxicity against NO-sensitive cells because (I) inhibition of NO production by activated macrophages reduces, not eliminates, cytotoxic ity; (2) NO produced chemically in amounts equimolar to those released from macrophages fails to lyse P815 cells; and (3) macrophages isolat ed from wounds 10 days after injury generate NO just as tumoricidal ac tivated macrophages but are not tumor cytotoxic, The noncytotoxic natu re of these wound-derived macrophages is not explained by the release of inactive forms of NO, because they suppress lymphocyte proliferatio n ill an NO-dependent manner, nor by the production of cytoprotective molecules, because their addition to activated macrophage-tumor cell c ocultures does not quench cytotoxicity. Interestingly, cytotoxicity ca n be aroused in day 10 wound-derived macrophages by culture with lipop olysaccharide, and macrophages harvested earlier ill tile development of the wound are cytotoxic, By generating NO but not killing an NO-sen sitive cell, day 10 wound-derived macrophages demonstrate that NO prod uction is not sufficient to account for the killing of an NO-sensitive tumor by macrophages.