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Abstract
Background: Recent clinical trials indicate that interferon-β (IFNβ) is effective in reducing exacerbations in relapsing–remitting MS, whereas IFNγ provokes acute relapses. However, the molecular mechanisms underlying the beneficial effects of IFNβ and the detrimental effects of IFNγ in MS remain to be characterized. Previously, the authors showed that IFNβ inhibited IFNγ-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 IFNβ, IFNγ, or IFNβ plus IFNγ.
Methods: Astrocytes were incubated for 24 hours in the culture medium with or without inclusion of 50 ng/mL recombinant human IFNβ, IFNγ, 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 IFNβ, both IRF-1 and intercellular adhesion molecule-1 mRNA mainly in astrocytes treated with IFNγ, and signal transducer and activator of transcription-1α and MHC class I HLA-C mRNA equally in astrocytes exposed to either type of IFN. In contrast, the treatment of astrocytes with either IFNβ or IFNγ 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 IFNβ and IFNγ in the pattern of gene induction in astrocytes.
Conclusion: A preferential induction of IRF-7 in IFNβ-treated astrocytes and a predominant expression of IRF-1 in IFNγ-exposed astrocytes might contribute to one of the molecular mechanisms underlying the clinically opposite effects of IFNβ and IFNγ in MS.
- Received December 4, 2000.
- Accepted April 20, 2001.
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