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in MS
From the Division of Neurology, Department of Internal Medicine, Saga Medical School, Japan.
Address correspondence and reprint requests to Dr. Jun-ichi Satoh, Division of Neurology, Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan; e-mail: satoj1{at}post.saga-med.ac.jp
Background:— Recent clinical trials indicate that interferon-ß (IFNß) is effective in reducing exacerbations in relapsing–remitting MS, whereas IFN
provokes acute relapses. However, the molecular mechanisms underlying the beneficial effects of IFNß and the detrimental effects of IFN in MS remain to be characterized. Previously, the authors showed that IFNß inhibited IFN-induced major histocompatibility complex (MHC) class II expression on astrocytes.
Objective:— To clarify the gene expression profile in cultured fetal human astrocytes after exposure to IFNß, IFN, or IFNß plus IFN.
Methods:— Astrocytes were incubated for 24 hours in the culture medium with or without inclusion of 50 ng/mL recombinant human IFNß, IFN, or both. The gene expression profile was studied by analyzing a cDNA expression array containing clones of various functional classes.
Results:— Among 1,185 clones examined, the expression of six distinct genes was markedly induced after IFN treatment. Northern blot analysis verified a significant up-regulation of mRNA for interferon regulatory factor-7 (IRF-7) and pleiotrophin predominantly in astrocytes treated with IFNß, both IRF-1 and intercellular adhesion molecule-1 mRNA mainly in astrocytes treated with IFN, and signal transducer and activator of transcription-1
and MHC class I HLA-C mRNA equally in astrocytes exposed to either type of IFN. In contrast, the treatment of astrocytes with either IFNß or IFN did not alter the levels of expression of mRNA for brain-derived neurotrophic factor, 27-kd heat shock protein, prion protein, or defender against apoptotic cell death-1. No antagonistic action was observed between IFNß and IFN in the pattern of gene induction in astrocytes.
Conclusion:— A preferential induction of IRF-7 in IFNß-treated astrocytes and a predominant expression of IRF-1 in IFN-exposed astrocytes might contribute to one of the molecular mechanisms underlying the clinically opposite effects of IFNß and IFN in MS.
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