IFN-β Inhibits Human Th17 Cell Differentiation

Abstract

IFN-
Inhibits Human Th17 Cell Differentiation1 Vinod S. Ramgolam,* Yonggang Sha,* Jianping Jin,† Xin Zhang,* and Silva Markovic-Plese2*‡ IFN-
-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-
-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-
-1a on dendritic cells (DCs) and naive CD4CD45RA T cells derived from untreated MS patients and healthy controls in the context of Th17 cell differentiation. We report that IFN-
-1a treatment down-regulated the expression of IL-1
and IL-23p19 in DCs, whereas it induced the gene expression of IL-12p35 and IL-27p28. We propose that IFN-
-1a-mediated up-regulation of the suppressor of cytokine signaling 3 expression, induced via STAT3 phosphorylation, mediates IL-1
and IL-23 down-regu- lation, while IFN-
-1a-induced STAT1 phosphorylation induces IL-27p28 expression. CD4CD45RA naive T cells cocul- tured with supernatants from IFN-
-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-
-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-
-1a inhibits IL-17 and induces IL-10 secretion via activated STAT1 and STAT3, respectively. IFN-
’s suppression of Th17 cell differentiation may represent its most relevant mechanism of selective suppression of the autoimmune response in MS. The Journal of Immu- nology, 2009, 183: 5418–5427. M ultiple sclerosis is an inflammatory demyelinatin

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Symptom Clusters