Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity

Macrophages use L-arginine to synthesize nitric oxide (NO) and polyamines t hrough the inducible NO synthase (iNOS) and arginase, respectively, The rel eased NO contributes to the tumoricidal activity of macrophages, whereas po lyamines may promote the growth of tumor cells. Both the tumoricidal and gr owth-promoting activities from macrophages have been reported; however, the underlying mechanisms for switching between this dual function of macropha ges remain unclear. Here, we test the hypothesis that arginase participates in the switching between the cytotoxic and growth-promoting activities of macrophages toward tumor cells. To alter arginase activity in macrophages, cells (murine macrophage cell line J774A.1) were transfected with the rat l iver arginase gene or treated with an arginase inhibitor, L-norvaline. The effects of macrophage arginase activity on the growth-promoting and cytotox ic activities of macrophages toward breast tumor cells (ZR-75-1) were inves tigated in a coculture system. The results demonstrated that overexpression of arginase in macrophages enhanced L-ornithine and putrescine production and consequently promoted tumor cell proliferation. This proliferative effe ct was down-regulated by the arginase inhibitor L-norvaline. Furthermore, i ncreases in arginase activity also attenuated NO production by the lipopoly saccharide-activated macrophages and thus reduced the cytotoxic effect on c ocultured tumor cells. Inhibiting arginase activity by L-norvaline effectiv ely reversed the suppression of NO-mediated tumor cytotoxicity, Together, t hese results suggest that arginase induction in macrophages can enhance tum or cell growth by providing them with polyamines and suppress tumor cytotox icity by reducing NO production. It appears that L-arginine metabolism thro ugh the arginase and iNOS pathways in macrophages can have very different i nfluences on the growth of nearby tumor cells depending on which pathway is prevailing.