Hibbs J B, Vavrin Z, Taintor R R
J Immunol. 1987 Jan 15;138(2):550-65.
L-Arginine is required for expression of the activated macrophage cytotoxic effector mechanism that causes inhibition of mitochondrial respiration, aconitase activity, and DNA synthesis in tumor target cells. This effector mechanism is active in the presence of L-arginine even when the cocultivation medium lacks all other amino acids and serum. Cytotoxic activated macrophage-induced inhibition of mitochondrial respiration in target cells is proportional to the concentration of L-arginine in the medium. L-Arginine must be present during the cocultivation period. Pretreatment of cytotoxic activated macrophages with L-arginine or posttreatment of the target cells after cocultivation is not effective. D-Arginine does not substitute for L-arginine and at high concentrations is a competitive inhibitor of the L-arginine-dependent effector mechanism. Other analogues that could not replace L-arginine include agmatine, argininic acid, arginine hydroxamate, and tosyl-L-arginine methyl ester. L-homoarginine, however, can effectively substitute for L-arginine. NG-monomethyl-L-arginine is a potent competitive inhibitor of this effector mechanism. High concentrations of lipopolysaccharide do not reverse inhibition of the L-arginine-dependent effector mechanism by NG-monomethyl-L-arginine. However, inhibition of the effector mechanism by NG-monomethyl-L-arginine can be overridden by increasing the concentration of L-arginine in the culture medium. We compared NGNG-dimethyl-L-arginine and NGN1G-dimethyl-L-arginine with NG-monomethyl-L-arginine as inhibitors of the L-arginine-dependent effector mechanism. The results show that the inhibitory effect of these guanidino methylated derivatives of L-arginine is highly determined by structure. Guanidine is a weak competitive inhibitor of the L-arginine-dependent effector mechanism. The requirement for L-arginine does not appear to be for protein synthesis, creatine biosynthesis, polyamine biosynthesis, or ADP ribosylation reactions. Bacterial lipopolysaccharide is effective as a second signal only when the cocultivation medium contains L-arginine, and this strict L-arginine dependency is not overridden by increasing the concentration of lipopolysaccharide. Bovine liver arginase, by competing for L-arginine in the cocultivation medium, inhibits the L-arginine-dependent activated macrophage cytotoxic effector mechanism.
L-精氨酸是激活巨噬细胞细胞毒性效应机制所必需的，该机制会抑制肿瘤靶细胞中的线粒体呼吸、乌头酸酶活性和DNA合成。即使共培养培养基缺乏所有其他氨基酸和血清，在L-精氨酸存在的情况下，这种效应机制仍然活跃。细胞毒性激活巨噬细胞诱导的靶细胞线粒体呼吸抑制与培养基中L-精氨酸的浓度成正比。L-精氨酸必须在共培养期间存在。用L-精氨酸预处理细胞毒性激活巨噬细胞或在共培养后对靶细胞进行后处理均无效。D-精氨酸不能替代L-精氨酸，高浓度时是L-精氨酸依赖性效应机制的竞争性抑制剂。其他不能替代L-精氨酸的类似物包括胍丁胺、精氨酸酸、精氨酸异羟肟酸和甲苯磺酰-L-精氨酸甲酯。然而，L-高精氨酸可以有效替代L-精氨酸。NG-单甲基-L-精氨酸是这种效应机制的有效竞争性抑制剂。高浓度的脂多糖不能逆转NG-单甲基-L-精氨酸对L-精氨酸依赖性效应机制的抑制作用。然而，通过增加培养基中L-精氨酸的浓度，可以克服NG-单甲基-L-精氨酸对效应机制的抑制作用。我们将NG，NG-二甲基-L-精氨酸和NG，N1-二甲基-L-精氨酸与NG-单甲基-L-精氨酸作为L-精氨酸依赖性效应机制的抑制剂进行了比较。结果表明，这些L-精氨酸的胍基甲基化衍生物的抑制作用高度取决于结构。胍是L-精氨酸依赖性效应机制的弱竞争性抑制剂。对L-精氨酸的需求似乎不是用于蛋白质合成、肌酸生物合成、多胺生物合成或ADP核糖基化反应。细菌脂多糖仅在共培养培养基含有L-精氨酸时才作为第二信号有效，并且这种严格的L-精氨酸依赖性不会因增加脂多糖的浓度而被克服。牛肝精氨酸酶通过在共培养培养基中竞争L-精氨酸，抑制L-精氨酸依赖性激活巨噬细胞细胞毒性效应机制。
