IFN-β Inhibits Human Th17 Cell Differentiation

Abstract

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.

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

“…Interestingly, mechanistic studies recently showed that IFN-β induced IL-10 in CD4 cells (13,16). Collectively, data indicate that reduction of IL-17 and induction of IL-10 seems to be important effects induced by IFN-β.…”

“…Also, Th17 cells showed a higher expression of type-1-interferon receptors as compared with Th1 cells, suggesting Th17 cells to be selectively targeted by IFN-β (12). The detailed mechanisms involved in IFN-β actions were recently reported including the ability of IFN-β to inhibit human Th17 cell differentiation (13), to inhibit IL-17-as well as osteopontin production in human CD4+ cells (11), and to inhibit IL-17 production by dendritic cells in MS patients, the latter mechanism probably mediated through IL-27 induction (14). We here report the longitudinal effects on IL-17A during INF-β treatment.…”

“…Thus, IFN-β was shown to reduce IL-17 production directly or indirectly by reduction of osteopontin and induction of IL-27 (10). Consequently, studies have demonstrated that IFN-β may exert its effect in MS by reduction of IL-17-associated immunity (11)(12)(13)(14). In contrast, it has been…”

B Cells as a Therapeutic Target for IFN-β in Relapsing–Remitting Multiple Sclerosis

“…Earlier studies have reported an increased expression of the Th17 cell-specific cytokine IL-17A in blood mononuclear cells during disease activity and in active MS lesions (5-7). We have recently reported a novel mechanism of IFN-b's suppression of Th17 cell differentiation through the inhibition of IL-1b and IL-23 and the induction of IL-12 and IL-27 expression in dendritic cells (DC) (8). Durelli et al (4) have proposed that IFN-b mediates apoptosis of Th17 cells because this cell subset exhibited an increased expression of IFN-type receptor chain 1 when compared with the Th1 cells.…”

TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

“…Indeed, it was shown that human Th17 lymphocytes can promote blood-brain barrier disruption and kill human neurons in vitro, suggesting a pathogenic role in MS (19). IFN-b1a, a commonly used disease-modifying immunotherapy for patients with relapsing-remitting MS (RRMS) (the phase of disease characterized by clinical relapses and remissions), is thought to exert at least part of its ameliorating effect through Th17 inhibition (20). In addition, complete abrogation of relapsing disease (both clinically and radiologically) after bone marrow transplantation was associated with selective reduction of Th17, but not Th1, responses (21).…”