PRETREATMENT OF ASTROCYTES WITH INTERFERON-ALPHA BETA IMPAIRS INTERFERON-GAMMA INDUCTION OF NITRIC-OXIDE SYNTHASE/

Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of incr eased astrocytic nitric oxide synthase activity in the postmortem brai n of multiple sclerosis patients supports this hypothesis. Exposure of astrocytes, in primary culture, to interferon-gamma results in stimul ation of nitric oxide synthase activity and increased nitric oxide rel ease. In contrast to interferon-gamma, interferon-alpha/beta had a min imal effect on astrocytic nitric oxide formation. Furthermore, pretrea tment of astrocytes with interferon-alpha/beta inhibited (similar to 6 5%) stimulation by interferon-gamma of nitric oxide synthase activity and nitric oxide release. Treatment with interferon-alpha/beta at a co ncentration as low as 10 U/ml caused inhibition of mitochondrial cytoc hrome c oxidase. Furthermore, the damage to cytochrome c oxidase was p revented by the putative interferon-alpha/beta receptor antagonist oxy phenylbutazone. In view of these observations, our current hypothesis is that the mitochondrial damage caused by exposure to interferon-alph a/beta may impair the ability of astrocytes to induce nitric oxide syn thase activity on subsequent interferon-gamma exposure. These results may have implications for our understanding of the mechanisms responsi ble for the therapeutic effects of interferon-alpha/beta preparations in multiple sclerosis.