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IFN-β Inhibits Human Th17 Cell Differentiation¹

Vinod S. Ramgolam,^* Yonggang Sha,^* Jianping Jin, Xin Zhang,^* and Silva Markovic-Plese^2*

^*Department of Neurology, Center for Bioinformatics, and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

IFN-β-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-β-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-β-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-β-1a treatment down-regulated the expression of IL-1β and IL-23p19 in DCs, whereas it induced the gene expression of IL-12p35 and IL-27p28. We propose that IFN-β-1a-mediated up-regulation of the suppressor of cytokine signaling 3 expression, induced via STAT3 phosphorylation, mediates IL-1β and IL-23 down-regulation, while IFN-β-1a-induced STAT1 phosphorylation induces IL-27p28 expression. CD4⁺CD45RA⁺ naive T cells cocultured with supernatants from IFN-β-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-β-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-β-1a inhibits IL-17 and induces IL-10 secretion via activated STAT1 and STAT3, respectively. IFN-β’s suppression of Th17 cell differentiation may represent its most relevant mechanism of selective suppression of the autoimmune response in MS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant K08 NS045871 and an Independent Medical Grant by EMD Serono Inc./Pfizer (to S.M.P.). A National MS Society Center Award (to S.M.P.) provided fellowship support for X.Z.

² Address correspondence and reprint requests to Dr. Silva Markovic-Plese, 6109 Neuroscience Research Building, 105 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. E-mail address: markovics{at}neurology.unc.edu

³ Abbreviations used in this paper: RR, relapsing-remitting; MS, multiple sclerosis; DC, dendritic cell; HC, healthy control; SOCS3, suppressor of cytokine signaling 3; SN, supernatant; RORc, retinoic acid-related orphan nuclear hormone receptor c; qRT-PCR, quantitative RT-PCR; FLUD, fludarabine; IFNAR, type I IFN receptor; EAE, experimental autoimmune encephalomyelitis.