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