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Differing effects of IFN beta vs IFN gamma in MS: gene expression in cultured astrocytes
1Division of Neurology, Department of Internal Medicine, Saga Medical School, Nabeshima, Japan. satoj1@post.saga-med.ac.jp
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.
Insights
Interferon-beta (IFN beta) preferentially induces IRF-7 in astrocytes, while interferon-gamma (IFN gamma) induces IRF-1. These distinct gene expression profiles in astrocytes may explain the differing effects of these interferons in multiple sclerosis (MS).
Area of Science:
- Neuroimmunology
- Molecular Biology
- Genetics
Background:
- Interferon-beta (IFN beta) reduces relapsing-remitting multiple sclerosis (MS) exacerbations, whereas IFN gamma can trigger relapses.
- The precise molecular mechanisms behind these opposing clinical effects of IFN beta and IFN gamma in MS are not fully understood.
- Previous research indicated IFN beta can inhibit IFN gamma-induced major histocompatibility complex (MHC) class II expression on astrocytes.
Purpose of the Study:
- To investigate the gene expression profiles in cultured human fetal astrocytes following exposure to IFN beta, IFN gamma, or a combination of both.
- To identify specific genes that are differentially regulated by IFN beta and IFN gamma in astrocytes.
Main Methods:
- Cultured fetal human astrocytes were treated with recombinant human IFN beta, IFN gamma, or both at 50 ng/mL for 24 hours.
- Gene expression profiles were analyzed using a cDNA expression array encompassing various functional gene classes.
- Northern blot analysis was employed to validate the mRNA expression levels of key induced genes.
Main Results:
- Treatment with IFN beta predominantly induced interferon regulatory factor-7 (IRF-7) and pleiotrophin mRNA.
- Treatment with IFN gamma primarily induced interferon regulatory factor-1 (IRF-1) and intercellular adhesion molecule-1 mRNA.
- Signal transducer and activator of transcription-1 alpha and MHC class I HLA-C mRNA were induced by both IFN beta and IFN gamma; no antagonistic effects were observed.
Conclusions:
- The preferential induction of IRF-7 by IFN beta and IRF-1 by IFN gamma in astrocytes suggests distinct molecular pathways.
- These differential gene expression patterns may contribute to the clinically observed opposing effects of IFN beta and IFN gamma in multiple sclerosis.
- Further research into these astrocyte-specific interferon responses could reveal novel therapeutic targets for MS.