Antiproliferative activity of gamma-interferon combined with lipopolysaccharide on murine adenocarcinoma: dependence on an L-arginine metabolism with production of nitrite and citrulline.

Growth of the murine adenocarcinoma EMT6 was moderately inhibited by up to 32 units/ml of gamma-interferon (IFN-gamma). However, EMT6 growth was blocked by as low as 2 U/ml of IFN-gamma, when added with lipopolysaccharide. In the same time, the combination IFN-gamma + lipopolysaccharide induced synergistically the production of nitrite and citrulline by EMT6 cells. Synthesis of the two products was correlated with IFN-gamma concentrations. It required exogenous L-arginine and was inhibited by a methylated L-arginine derivative, NG-monomethyl-L-arginine. Inhibition was specific since urea synthesis was not reduced by NG-monomethyl-L-arginine. The L-arginine-dependent pathway was involved in EMT6 cytostasis mediated by IFN-gamma + lipopolysaccharide because cytostasis expression required L-arginine and was inhibited by NG-monomethyl-L-arginine.