Abstract
IFN-beta-1a has been used over the past 15 years as a primary therapy for relapsing-remitting multiple sclerosis (MS). However, the immunomodulatory mechanisms that provide a therapeutic effect against this CNS inflammatory disease are not yet completely elucidated. The effect of IFN-beta-1a on Th17 cells, which play a critical role in the development of the autoimmune response, has not been extensively studied in humans. We have investigated the effect of IFN-beta-1a on dendritic cells (DCs) and naive CD4(+)CD45RA(+) T cells derived from untreated MS patients and healthy controls in the context of Th17 cell differentiation. We report that IFN-beta-1a treatment down-regulated the expression of IL-1beta and IL-23p19 in DCs, whereas it induced the gene expression of IL-12p35 and IL-27p28. We propose that IFN-beta-1a-mediated up-regulation of the suppressor of cytokine signaling 3 expression, induced via STAT3 phosphorylation, mediates IL-1beta and IL-23 down-regulation, while IFN-beta-1a-induced STAT1 phosphorylation induces IL-27p28 expression. CD4(+)CD45RA(+) naive T cells cocultured with supernatants from IFN-beta-1a-treated DCs exhibited decreased gene expression of the Th17 cell markers retinoic acid-related orphan nuclear hormone receptor c (RORc), IL-17A, and IL-23R. A direct IFN-beta-1a treatment of CD45RA(+) T cells cultured in Th17-polarizing conditions also down-regulated RORc, IL-17A, and IL-23R, but up-regulated IL-10 gene expression. Studies of the mechanisms involved in the Th17 cell differentiation suggest that IFN-beta-1a inhibits IL-17 and induces IL-10 secretion via activated STAT1 and STAT3, respectively. IFN-beta's suppression of Th17 cell differentiation may represent its most relevant mechanism of selective suppression of the autoimmune response in MS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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Cell Differentiation / drug effects*
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Cell Differentiation / immunology
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Cells, Cultured
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Down-Regulation / drug effects
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Down-Regulation / immunology
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Humans
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Interferon beta-1a
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Interferon-beta / pharmacology*
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Interleukin-10 / agonists
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-12 Subunit p35 / agonists
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Interleukin-12 Subunit p35 / immunology
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Interleukin-12 Subunit p35 / metabolism
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Interleukin-17 / immunology*
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Interleukin-23 Subunit p19 / antagonists & inhibitors
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Interleukin-23 Subunit p19 / immunology
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Interleukin-23 Subunit p19 / metabolism
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Multiple Sclerosis / immunology*
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Phosphorylation / drug effects
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Phosphorylation / immunology
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Receptors, CCR6 / antagonists & inhibitors
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Receptors, CCR6 / immunology
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Receptors, CCR6 / metabolism
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Receptors, Interleukin / antagonists & inhibitors
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Receptors, Interleukin / immunology
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Receptors, Interleukin / metabolism
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Receptors, Retinoic Acid / immunology
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Receptors, Retinoic Acid / metabolism
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Receptors, Thyroid Hormone / immunology
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Receptors, Thyroid Hormone / metabolism
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STAT1 Transcription Factor / drug effects
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STAT1 Transcription Factor / immunology
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STAT1 Transcription Factor / metabolism
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STAT3 Transcription Factor / drug effects
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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T-Lymphocytes, Helper-Inducer / drug effects*
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T-Lymphocytes, Helper-Inducer / immunology
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Up-Regulation / drug effects
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Up-Regulation / immunology
Substances
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CCR6 protein, human
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IL23R protein, human
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Interleukin-12 Subunit p35
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Interleukin-17
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Interleukin-1beta
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Interleukin-23 Subunit p19
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RORC protein, human
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Receptors, CCR6
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Receptors, Interleukin
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Interleukin-10
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Interferon-beta
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Interferon beta-1a