The flavonoid kurarinone inhibits clinical progression of EAE through inhibiting Th1 and Th17 cell differentiation and proliferation


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Abstract

IntroductionThe flavonoid kurarinone suppresses CD4+ T-cell-mediated chronic inflammatory dermatitis. However, kurarinone's effects upon autoimmune central nervous system (CNS) disease remain unknown. We investigated the potential therapeutic effects and molecular mechanism(s) of kurarinone in an experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis (MS).Materials and methodsMyelin oligodendrocyte glycoprotein (MOG35-55) peptide-induced EAE was constructed in wild-type mice. Effects of kurarinone (100 mg/kg/day) upon clinical scores were assessed based on physical traits and signs. Spinal cord sections were extracted to assess inflammation, demyelination, and mRNA expression of key pro-inflammatory cytokines and chemokines. CNS-infiltrating mononuclear cells (MNCs) and splenocytes were harvested; flow cytometry was then applied to determine CD4+ and CD8+ T-cell percentages as well as Th1/Th2/Th17 subset percentages. Purified naïve CD4+ T-cells underwent in vitro T-cell polarization and proliferation to assess kurarinone's effects.ResultsProphylactic and treatment regimens of kurarinone significantly improved clinical scores in the MOG35-55 peptide-induced EAE model (P< 0.05). Kurarinone significantly lowered CNS inflammation and demyelination (61% and 83% decreases, respectively; P< 0.05), significantly decreased MNC infiltration into CNS tissue (42% decrease; P< 0.05), and significantly inhibited levels of several pro-inflammatory cytokines and chemokines (P< 0.05). Kurarinone significantly lowered CD4+ and CD8+ CNS T-cell counts (51% and 80% decreases, respectively; P < 0.05) and significantly reduced CNS Th1 and Th17 cell percentages (24% and 44% decreases, respectively; P< 0.05). Kurarinone significantly inhibited in vitro Th1, Th2, and Th17 cell differentiation and proliferation (P< 0.05).ConclusionsKurarinone significantly inhibits the clinical progression of EAE through the inhibition of Th1 and Th17 cell differentiation and proliferation. Kurarinone may show promise as an immunomodulatory therapeutic agent in treating MS.HighlightsKurarinone's effects upon the MOG peptide-induced EAE model of MS were assessed.Kurarinone improved clinical scores, CNS inflammation, and CNS demyelination.Kurarinone decreased CNS MNC infiltration and inflammatory cytokines/chemokines.Kurarinone lowered CNS and splenic Th1 and Th17 cell percentages.Kurarinone inhibited Th1, Th2, and Th17 cell differentiation and proliferation.

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