Wong G H
Genentech, Inc., South San Francisco, CA 94080, USA.
Biochim Biophys Acta. 1995 May 24;1271(1):205-9. doi: 10.1016/0925-4439(95)00029-4.
Oxidative stress such as radiation can trigger the production of cytokines including tumor necrosis factor (TNF) and lymphotoxin (LT). The increased cytokine levels may in turn induce the synthesis of protein(s) that protect against subsequent killing by oxidative stress. Indeed, pretreatment of animals with TNF or LT can protect them against lethal doses of radiation and the alopecia that results from anticancer drugs. TNF or LT can specifically and selectively induce the expression of manganous superoxide dismutase (MnSOD). MnSOD, identified as one of the protective proteins, is a mitochondrial enzyme that scavenges superoxide radicals (O2-). TNF-R1 but not TNF-R2 is responsible for TNF and LT's induction of MnSOD. Paradoxically, the TNF-R1 is also the receptor that mediates the production of oxygen free radicals and apoptosis. Overexpression of MnSOD but not CuZn-SOD or EC-SOD enhances cellular resistance to radiation. Conversely, overexpression of antisense MnSOD RNA diminishes resistance. Transfection of cells with MnSOD lacking the mitochondrial matrix signal does not provide protection against radiation. However, insertion of the mitochondrial signal sequence into CuZn-SOD or EC-SOD results in significant protection. TNF or LT does not induce MnSOD in tumor cells; nor do they protect these cells against radiation. Actually, TNF or LT pretreatment can sensitize tumor cells to killing by radiation.
诸如辐射之类的氧化应激可触发包括肿瘤坏死因子（TNF）和淋巴毒素（LT）在内的细胞因子的产生。细胞因子水平的升高反过来可能诱导蛋白质的合成，这些蛋白质可保护细胞免受随后氧化应激的杀伤。事实上，用TNF或LT对动物进行预处理可保护它们免受致死剂量辐射以及抗癌药物导致的脱发影响。TNF或LT可特异性且选择性地诱导锰超氧化物歧化酶（MnSOD）的表达。MnSOD被确定为一种保护性蛋白质，是一种清除超氧阴离子自由基（O2-）的线粒体酶。TNF-R1而非TNF-R2负责TNF和LT对MnSOD的诱导。矛盾的是，TNF-R1也是介导氧自由基产生和细胞凋亡的受体。MnSOD的过表达而非铜锌超氧化物歧化酶（CuZn-SOD）或细胞外超氧化物歧化酶（EC-SOD）的过表达可增强细胞对辐射的抗性。相反，反义MnSOD RNA的过表达会降低抗性。用缺乏线粒体基质信号的MnSOD转染细胞不能提供对辐射的保护。然而，将线粒体信号序列插入CuZn-SOD或EC-SOD会产生显著的保护作用。TNF或LT不会在肿瘤细胞中诱导MnSOD；它们也不能保护这些细胞免受辐射。实际上，TNF或LT预处理可使肿瘤细胞对辐射杀伤敏感。
