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Pretreatment of Astrocytes with Interferon‐α/β Impairs Interferon‐γ Induction of Nitric Oxide Synthase
Author(s) -
Stewart Victoria C.,
Giovani Gavin,
Land John M.,
McDonald W. Ian,
Clark John B.,
Heales Simon J. R.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68062547.x
Subject(s) - nitric oxide synthase , interferon , nitric oxide , chemistry , neuroscience , interferon γ , immunology , interferon gamma , biology , cytokine , organic chemistry
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‐γ results in stimulation of nitric oxide synthase activity and increased nitric oxide release. In contrast to interferon‐γ, interferon‐α/β had a minimal effect on astrocytic nitric oxide formation. Furthermore, pretreatment of astrocytes with interferon‐α/β inhibited (∼65%) stimulation by interferon‐γ of nitric oxide synthase activity and nitric oxide release. Treatment with interferon‐α/β 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‐α/β receptor antagonist oxyphenylbutazone. In view of these observations, our current hypothesis is that the mitochondrial damage caused by exposure to interferon‐α/β may impair the ability of astrocytes to induce nitric oxide synthase activity on subsequent interferon‐γ exposure. These results may have implications for our understanding of the mechanisms responsible for the therapeutic effects of interferon‐α/β preparations in multiple sclerosis.