Abstract
Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophora flavescens, suppresses experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), by inducing the production of immunomodulatory molecules, e.g., IL-10. In an effort to find the upstream pathway(s) of the mechanism underlying these effects, we have tested certain upregulated immunomodulatory molecules. Among them, we found increased levels of IL-27 and IFN-β, one of the first-line MS therapies. Indeed, while low levels of IFN-β production in sera and type I interferon receptor (IFNAR1) expression in spinal cord of saline-treated control EAE mice were detected, they were significantly increased after MAT treatment. Increased numbers of CD11b+IFN-β+ microglia/infiltrating macrophages were observed in the CNS of MAT-treated mice. The key role of IFN-β induction in the suppressive effect of MAT on EAE was further verified by administration of anti-IFN-β neutralizing antibody, which largely reversed the therapeutic effect of MAT. Further, we found that, while MAT treatment induced production of IL-27 and IL-10 by CNS microglia/macrophages, this effect was significantly reduced by IFN-β neutralizing antibody. Finally, the role of IFN-β in MAT-induced IL-27 and IL-10 production was further confirmed in human monocytes in vitro. Together, our study demonstrates that MAT exerts its therapeutic effect in EAE through an IFN-β/IL-27/IL-10 pathway, and is likely a novel, safe, low-cost, and effective therapy as an alternative to exogenous IFN-β for MS.
Highlights
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory demyelinating diseases of the central nervous system (CNS) [1, 2]
We found that only a few CD11b+IL-27+ cells were observed in EAE mice treated with saline or anti-IFN-β alone, while they were observed in a larger number in MAT-treated mice
In the present study we demonstrate that MAT induced IFN-β production, which promoted production IL-27 and IL-10, and is a mechanism of the immunomodulatory effects of MAT in suppressing the development of EAE
Summary
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory demyelinating diseases of the central nervous system (CNS) [1, 2]. The pathological features of MS are immune system imbalance, CNS inflammation, demyelination and neuro-axonal damage [3,4,5,6]. In the CNS, these cells produce proinflammatory cytokines IFN-γ, IL-17, GM-CSF, and IL-23, activate. Matrine Inhibited EAE by IFN-β Induction microglia, and promote cell- and antibody-mediated immunity. Immunoregulatory cytokines, such as IL-4, IL-10, and IL-27, may be protective [1, 2]. The effectiveness of current therapies is limited [7, 8]. Novel therapies for MS that are more effective, and with fewer side effects than those currently in use are, crucially required
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