Alteration of physiological activity of activated macrophages through L-arginine metabolism.

Our aim in this study was to define the effect of L-arginine on macrophages (M phi) in relation to the decay of tumoricidal activity of activated M phi. We found that the activated M phi retained their cytotoxicity when cultured in L-arginine-deficient medium but not in conventional medium. Such a decline of tumoricidal activity was associated with increase of glucose consumption and concomitant lactate production, resulting in M phi death. Addition of glucose to the culture medium of activated M phi appeared to cause only a slight delay of the decrease of tumoricidal activity and M phi death. These events were also coincident with a decrease of electron transport activity in mitochondria. Cytological observation by electron microscopy clearly showed the structural alteration or destruction of mitochondria, which preceded the changes of other physiological and functional activities. These results demonstrate that the L-arginine-dependent cytolytic activity against tumor target cells also impairs M phi functions and ultimately induces M phi death, which is primarily mediated by the inhibition of mitochondrial activity.

macrophage(s)

MEM depleted of L‐arginine

lipopolysaccharide

normal MEM

thioglycollate broth

lactate dehydrogenase