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.