Stewart V C, Giovannoni G, Land J M, McDonald W I, Clark J B, Heales S J
Department of Neurochemistry, Institute of Neurology, National Hospital of Neurology and Neurosurgery, London, England.
J Neurochem. 1997 Jun;68(6):2547-51. doi: 10.1046/j.1471-4159.1997.68062547.x.
Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of increased astrocytic nitric oxide synthase activity in the postmortem brain of multiple sclerosis patients supports this hypothesis. Exposure of astrocytes, in primary culture, to interferon-gamma results in stimulation of nitric oxide synthase activity and increased nitric oxide release. In contrast to interferon-gamma, interferon-alpha/beta had a minimal effect on astrocytic nitric oxide formation. Furthermore, pretreatment of astrocytes with interferon-alpha/beta inhibited (approximately 65%) stimulation by interferon-gamma of nitric oxide synthase activity and nitric oxide release. Treatment with interferon-alpha/beta at a concentration as low as 10 U/ml caused inhibition of mitochondrial cytochrome c oxidase. Furthermore, the damage to cytochrome c oxidase was prevented by the putative interferon-alpha/beta receptor antagonist oxyphenylbutazone. In view of these observations, our current hypothesis is that the mitochondrial damage caused by exposure to interferon-alpha/beta may impair the ability of astrocytes to induce nitric oxide synthase activity on subsequent interferon-gamma exposure. These results may have implications for our understanding of the mechanisms responsible for the therapeutic effects of interferon-alpha/beta preparations in multiple sclerosis.
过量一氧化氮/过氧亚硝酸盐的产生与多发性硬化症的发病机制有关，多发性硬化症患者死后大脑中星形胶质细胞一氧化氮合酶活性增加的证据支持了这一假说。在原代培养中，星形胶质细胞暴露于γ干扰素会导致一氧化氮合酶活性受到刺激，一氧化氮释放增加。与γ干扰素相反，α/β干扰素对星形胶质细胞一氧化氮的形成影响极小。此外，用α/β干扰素预处理星形胶质细胞可抑制（约65%）γ干扰素对一氧化氮合酶活性和一氧化氮释放的刺激。低至10 U/ml浓度的α/β干扰素处理会导致线粒体细胞色素c氧化酶受到抑制。此外，推测的α/β干扰素受体拮抗剂羟苯基丁唑可防止细胞色素c氧化酶受到损伤。鉴于这些观察结果，我们目前的假说是，暴露于α/β干扰素所导致的线粒体损伤可能会损害星形胶质细胞在随后暴露于γ干扰素时诱导一氧化氮合酶活性的能力。这些结果可能对我们理解α/β干扰素制剂在多发性硬化症中的治疗作用机制具有启示意义。
