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

Abstract

Macrophages use L-arginine to synthesize nitric oxide (NO) and polyamines through the inducible NO synthase (iNOS) and arginase, respectively. The released NO contributes to the tumoricidal activity of macrophages, whereas polyamines may promote the growth of tumor cells. Both the tumoricidal and growth-promoting activities from macrophages have been reported; however, the underlying mechanisms for switching between this dual function of macrophages 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 liver arginase gene or treated with an arginase inhibitor, L-norvaline. The effects of macrophage arginase activity on the growth-promoting and cytotoxic activities of macrophages toward breast tumor cells (ZR-75-1) were investigated 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 effect was down-regulated by the arginase inhibitor L-norvaline. Furthermore, increases in arginase activity also attenuated NO production by the lipopolysaccharide-activated macrophages and thus reduced the cytotoxic effect on cocultured tumor cells. Inhibiting arginase activity by L-norvaline effectively reversed the suppression of NO-mediated tumor cytotoxicity. Together, these results suggest that arginase induction in macrophages can enhance tumor cell growth by providing them with polyamines and suppress tumor cytotoxicity by reducing NO production. It appears that L-arginine metabolism through the arginase and iNOS pathways in macrophages can have very different influences on the growth of nearby tumor cells depending on which pathway is prevailing.