Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Abstract

IFN-b currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-b on the regulation of OPN and IL-17 in MS patients. We found that IFN-b used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4 1 T-cell level. In addition, IFN-b inhibited the production of IL-17 and IL-21 in CD4 1 T cells. It has been described that IFN-b suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-b also acted directly on the CD4 1 T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-b to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN 1 and IL-17 1 cells decreased in IFN-b-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-b treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-b treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-b in the treatment of MS. IntroductionMS is a disease of the CNS characterized by chronic inflammatory and demyelinating processes [1]. CNS inflammation is considered as an important feature in MS pathology, and is directly associated with the disease process in MS [2]. Agents that have anti-inflammatory properties have been shown to suppress the disease activity to various degrees. MS is now commonly treated with an immunomodulatory agent, IFN-b, which has shown significant treatment efficacy and is à These authors contributed equally to the work. Eur. J. Immunol. 2009. 39: 2525-2536 Immunomodulation 2525 thought to involve a number of different mechanisms of action [3,4]. However, despite extensive clinical experience in the use of IFN-b, its mechanism of action has not been fully elucidated. Studies into its mechanism of action have revealed that anti-inflammatory properties of IFN-b function through the regulation of Th1 and Th2 cytokines [5,6]. Further, there is an evidence indicating that IFN-b promotes the production of IL-10 and inhibits the action of pro-inflammatory cytokines [7,8].Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages...

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, these finding mirror changes as predicted by detailed in vitro mechanistic studies of IL-17 (9)(10)(11)(12)14) and . Another main finding of our study was the potential difference between responders and non-responders in IL-17A levels before and after 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…”

Cerebrospinal Fluid IL-21 Levels in Neuromyelitis Optica and Multiple Sclerosis

“…IFN-β, currently serving as one of the major treatments for MS, used in vitro significantly inhibited the production of Il-21 in CD4 + T cells derived from PBMC. Administration of IFN-β to eAe mice ameliorated the disease severity along with decreases in serum levels of Il-21 26 . Other novel therapies, such as simvastatin 27 , curcumin 28 , DNA vaccine 29 , also ameliorated eAe by down-regulating expression of Il-21.…”

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

“…Consistent with the reduced IL-17 serum levels in the um-PEA-treated group, we also found reduced TNF-α serum levels. Importantly, this effect is obtained under IFN-β1a treatment, which per se reduces the proinflammatory cytokine serum levels in MS [52][53][54]. Inflammatory mediators, such as IFN-γ and TNF-α are known key contributors to the induction and maintenance of autoimmune diseases [55][56][57][58].…”