MECHANISMS OF KUPFFER CELL CYTOTOXICITY IN-VITRO AGAINST THE SYNGENEIC MURINE COLON ADENOCARCINOMA LINE MCA26

We have previously demonstrated that in vivo activation or inhibition of Kupffer cell (KC) cytotoxic function can reduce or enhance, respect ively, the hepatic tumor burden in a syngeneic murine colon adenocarci noma (MCA26) tumor model. In the current study, we have performed in v itro experiments to define the possible mechanisms of KC cytotoxicity against MCA26 cells. Addition of either anti-tumor necrosis factor (TN F) or anti-interleukin-1alpha (IL-1alpha) antisera reduced KC cytotoxi city in coculture against MCA26 targets in a dose-dependent fashion; a ddition of these sera together resulted in approximately additive inhi bition, suggesting the existence of parallel pathways for these effect or molecules. Nitric oxide as a mediator of cytotoxicity by KCs in coc ulture with MCA26 cells was evaluated by two approaches. Activated KCs produced detectable levels of nitric oxide; however, activated KC exe rted cytotoxicity against MCA26 targets in the absence of exogenous fr ee L-arginine. Thus, TNF and IL-1 play major roles in producing murine KC cytotoxicity against MCA26 colon cancer cells in vitro, whereas re active nitric oxides do not.