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.
Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Vinod S
VS
Ramgolam
Yonggang
Y
Sha
Jianping
J
Jin
Xin
X
Zhang
Silva
S
Markovic-Plese
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