IFN-beta inhibits human Th17 cell differentiation.
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.
Ramgolam
Vinod S
VS
Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sha
Yonggang
Y
Jin
Jianping
J
Zhang
Xin
X
Markovic-Plese
Silva
S
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000494:pharmacology*; D016753:Interleukin-10 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D054399:Receptors, CCR6 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C106311:CCR6 protein, human; C515500:IL23R protein, human; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17; D053583:Interleukin-1beta; D053760:Interleukin-23 Subunit p19; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D054399:Receptors, CCR6; D018123:Receptors, Interleukin; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D016899:Interferon-beta; D000068556:Interferon beta-1a