Synergistic effect of β-amyloid protein and interferon gamma on nitric oxide production by C2C12 muscle cells
Synergistic effect of β-amyloid protein and interferon gamma on nitric oxide production by C2C12 muscle cells
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DOI：
10.1093/brain/123.2.374
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发表时间：
2000-02-01
期刊：
影响因子：
14.5
通讯作者：
Scarlato, G
中科院分区：
文献类型：
--
作者：
Baron, P;Galimberti, D;Scarlato, G
一氧化氮（NO）是多种生理和病理反应的重要介质，NO诱导的氧化应激在包涵体肌炎（IBM）肌肉组织损伤的发病机制中被提出，其特征是空泡化肌纤维中β -淀粉样蛋白（A β）的沉积。我们在体外用A β[1-42]或A β[25-35]肽刺激C2C12小鼠骨骼肌细胞，无论是否存在干扰素γ (ifn - γ)。单独给药时，A β肽和ifn - γ都不能刺激C2C12细胞产生亚硝酸盐（NO2-），然而，ifn - γ与A β[1-42]或A β[25-35]联合使用可导致NO2-释放到无细胞的上清液中。从A β / ifn - γ刺激的C2C12细胞中获得的RNA进行Northern blot分析发现，诱导型一氧化氮合酶（iNOS） mRNA积累增加，此外，与4%的A β肽和ifn - γ培养的肌肉细胞相似，显示出DNA断裂的超微结构特征，这些结果表明，A β与ifn - γ的关联通过诱导iNOS基因表达来刺激骨骼肌细胞中NO2-的产生。偶尔有证据表明核变化提示凋亡形态，这些数据进一步支持a - β沉积在IBM中假定的氧化损伤发病机制中的作用。
Nitric oxide (NO) is an important mediator of diverse physiological and pathological responses, NO-induced oxidative stress has been proposed in the pathogenesis of muscle tissue damage in inclusion-body myositis (IBM), which is characterized by deposition of beta-amyloid protein (A beta) in vacuolated muscle fibres, To determine whether A beta can induce NO production in skeletal muscle, we stimulated C2C12 mouse skeletal muscle cells in vitro with A beta[1-42] or A beta[25-35] peptides in the presence or absence of interferon gamma (IFN-gamma). Neither A beta peptides nor IFN-gamma were able to stimulate nitrite (NO2-) production by C2C12 cells when given alone, However, combination of IFN-gamma with either A beta[1-42] or A beta[25-35] resulted in significant NO2- release into cell-free supernatants. Northern blot analysis of RNA obtained from A beta/IFN-gamma-stimulated C2C12 cells revealed increased mRNA accumulation of inducible nitric oxide synthase (iNOS), Moreover, similar to 4% of muscle cells incubated with A beta peptides and IFN-gamma showed ultrastructural features of DNA fragmentation, These findings, taken together, indicate that the association of A beta with IFN-gamma stimulates NO2- production via induction of iNOS gene expression in skeletal muscle cells, with occasional evidence for nuclear changes suggesting apoptotic morphology, These data further support a role for A beta deposition in the pathogenesis of postulated oxidative damage in IBM.