Macrophage arginine metabolism and the inhibition or stimulation of cancer.
Macrophage arginine metabolism and the inhibition or stimulation of cancer.
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DOI：
10.4049/jimmunol.149.8.2709
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发表时间：
1992-10
影响因子：
4.4
通讯作者：
C. Mills;J. Shearer;R. Evans;M. Caldwell
中科院分区：
文献类型：
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作者：
C. Mills;J. Shearer;R. Evans;M. Caldwell
免疫系统抑制或刺激肿瘤生长的潜力是免疫应答的“双刃剑”性质的生动例子。我们的研究结果提供的证据表明，这种双重能力可以部分归因于肿瘤内巨噬细胞所表现出的精氨酸代谢的双重途径。具体而言，P815预免疫小鼠腹腔内肿瘤排斥反应伴随着肿瘤内巨噬细胞精氨酸代谢向一氧化氮（NO）合酶途径的上调，该途径产生瓜氨酸和NO。在肿瘤排斥反应期间，预免疫小鼠IFN-γ（mRNA和蛋白质）的快速和显著局部增加表明该细胞因子在体内上调一氧化氮产生中发挥作用。与肿瘤排斥不同，幼稚小鼠中进行性腹膜内P815肿瘤生长与肿瘤内巨噬细胞产生瓜氨酸/NO的显著下降相关。巨噬细胞精氨酸代谢的检查，通过精氨酸酶显示了相反的模式，NO合酶。在进行性肿瘤生长期间，局部产生的鸟氨酸/尿素显著增加，而在肿瘤排斥期间，鸟氨酸酶活性降低。由于一氧化氮抑制肿瘤细胞复制，而鸟氨酸是细胞复制所需的多胺的前体，这些结果与巨噬细胞用于代谢精氨酸的途径可以影响针对癌症和其他病症的宿主免疫应答的类型的结论一致。
The potential of the immune system to inhibit or stimulate tumor growth is a vivid example of the "two-edged sword" nature of immune responses. Our results provide evidence that this dual capacity can be attributed, in part, to the dual pathways of arginine metabolism exhibited by intratumor macrophages. Specifically, i.p. tumor rejection in P815-preimmunized mice is accompanied by an upshift in intratumor macrophage arginine metabolism to the nitric oxide (NO) synthase pathway that yields citrulline and NO. A rapid and marked local increase in IFN-gamma (both mRNA and protein) in preimmunized mice during tumor rejection suggests that this cytokine plays a role in up-regulating nitric oxide production in vivo. Unlike tumor rejection, progressive i.p. P815 tumor growth in naive mice is associated with a marked decline in the production of citruline/NO by intratumor macrophages. Examination of macrophage arginine metabolism via arginase revealed a pattern opposite that of NO synthase. The local production of ornithine/urea markedly increases during progressive tumor growth whereas arginase activity decreases during tumor rejection. Inasmuch as nitric oxide inhibits tumor cell replication whereas ornithine is the precursor of polyamines required for cell replication, these results are consistent with the conclusion that the pathway macrophages use to metabolize arginine can influence the type of host immune responses against cancer and other conditions.