Rieger J, Ständer M, Löschmann P A, Heneka M, Dichgans J, Klockgether T, Weller M
Department of Neurology, University of Tübingen, School of Medicine, Germany.
Oncogene. 1998 Nov 5;17(18):2323-32. doi: 10.1038/sj.onc.1202154.
Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-beta or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.
一氧化氮（NO）被认为在哺乳动物大脑的神经传递、炎症和细胞死亡调节中发挥重要作用。在此，我们研究了人类恶性胶质瘤细胞中NO的合成及生物学效应。暴露于细胞因子如干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α或白细胞介素（IL）-1β以及脂多糖（LPS）可诱导大鼠C6和A172人类胶质瘤细胞中NO的合成，但在LN-229、T98G或LN-18人类恶性胶质瘤细胞中则不会。诱导释放的NO涉及诱导型一氧化氮合酶（iNOS）表达的增强。通过中和内源性转化生长因子-β（TGF-β）或同时暴露于细胞因子、LPS和抗氧化剂，并不能克服在后者细胞系中检测不到NO释放的情况。CD95配体（CD95L）诱导的凋亡不涉及NO的形成。一氧化氮合酶抑制剂和NO供体均未调节CD95L诱导的凋亡。地塞米松（DEX）介导的对胶质瘤细胞免受CD95L诱导凋亡的保护作用也与DEX对NO代谢的影响无关。DEX不仅抑制细胞因子/LPS诱导的NO释放，还减弱了NO在五个细胞系中的三个细胞系中的毒性。在C6细胞中强制表达温度敏感型p53 val135的突变型或野生型构象均抑制细胞因子/LPS诱导的NO合成。此外，突变型或野生型构象的p53积累均可保护胶质瘤细胞免受外源性NO的毒性，这与p53积累相关的p53功能获得一致。我们得出结论，对NO依赖性免疫防御机制的抗性可能有助于p53改变的人类癌症的恶性进展，特别是那些与突变型p53蛋白积累相关的癌症。
