Southern C, Matthews N
Yamanouchi Research Institute, Oxford, UK.
Biochim Biophys Acta. 1993 Jun 6;1177(2):179-82. doi: 10.1016/0167-4889(93)90038-q.
Proinflammatory cytokines, including TNF, stimulate nitric-oxide free radical production in a variety of tissues through the induction of the enzyme nitric-oxide synthase. As free radicals are considered likely candidates in the cytotoxic action of TNF, we examined nitric oxide production in TNF-sensitive U937A and TNF-resistant U937A/R cells and its potential role in TNF-induced cytotoxicity. TNF stimulated U937A nitrite production through a process that was abolished by the competitive inhibitors of nitric-oxide synthase N-omega-nitro-L-arginine methyl ester (NAME) and N-G-monomethyl-L-arginine (NMMA) without inhibition of TNF-induced cytotoxicity. TNF also increased nitrite production in TNF-resistant U937A/R cells. In addition, the cytotoxic action of TNF was independent of L-arginine substrate availability. Thus, although cytokine-inducible nitric oxide production is emerging as an effective antitumour mechanism, here, TNF clearly exerted potent antitumour activity against U937A cells through a nitric-oxide-independent mechanism.
包括肿瘤坏死因子（TNF）在内的促炎细胞因子，通过诱导一氧化氮合酶，刺激多种组织中一氧化氮自由基的产生。由于自由基被认为可能是TNF细胞毒性作用的候选因素，我们检测了TNF敏感的U937A细胞和TNF耐药的U937A/R细胞中一氧化氮的产生及其在TNF诱导的细胞毒性中的潜在作用。TNF通过一氧化氮合酶的竞争性抑制剂N-ω-硝基-L-精氨酸甲酯（NAME）和N-G-单甲基-L-精氨酸（NMMA）所阻断的过程刺激U937A细胞产生亚硝酸盐，而不抑制TNF诱导的细胞毒性。TNF也增加了TNF耐药的U937A/R细胞中亚硝酸盐的产生。此外，TNF的细胞毒性作用与L-精氨酸底物的可用性无关。因此，尽管细胞因子诱导的一氧化氮产生正成为一种有效的抗肿瘤机制，但在这里，TNF显然通过一种不依赖一氧化氮的机制对U937A细胞发挥了强大的抗肿瘤活性。
