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1,25-Dihydroxyvitamin D3 (1,25(OH) 2 D 3 ) suppresses autoimmunity and inflammation; however, the mechanism of its action has not been fully understood. We sought in this study to determine whether the anti-immune/anti-inflammatory action of 1,25(OH) 2 D 3  is in part mediated through an interplay between 1,25(OH) 2 D 3  and toll-like receptor (TLR)7/8 signaling. 1,25(OH) 2 D 3  treatment prior to and/or following experimental autoimmune encephalomyelitis (EAE) induction effectively reduced inflammatory cytokine expression in the spinal cord and ameliorated EAE. These effects were accompanied with a reduction in expression of several TLRs with the most profound effect observed for TLR8. The expression of TLR8 adaptor protein MyD88 was also significantly reduced by 1,25(OH) 2 D 3 . To determine the molecular mechanism by which 1,25(OH) 2 D 3  suppresses EAE induction of TLR8 and inflammatory cytokine expression, we evaluated whether 1,25(OH) 2 D 3  can directly inhibit TLR8 signaling and the resulting inflammatory responses in human THP-1 monocytes. 1,25(OH) 2 D 3  treatment not only significantly reduced TLR8 expression but also the expression or activity of MyD88, IRF-4, IRF-7 and NF-kB in monocytes challenged with TLR8 ligands. TLR8 promoter-luciferase reporter assays indicated that 1,25(OH) 2 D 3  decreases TLR8 mRNA level in part via inhibiting TLR8 gene transcription activity. As a result of inhibition on TLR8 signaling cascade at various stages, 1,25(OH) 2 D 3  significantly diminished the TLR8 target gene expression (TNF-α and IL-1β). In summary, our novel findings suggest that TLR8 is a new target of 1,25(OH) 2 D 3  and may mediate the anti-inflammatory action of 1,25(OH) 2 D 3 . Our findings also point to a destructive role of TLR8 in EAE and shed lights on pathogenesis of multiple sclerosis.

plos one

1,25-Dihydroxyvitamin D3 Suppresses TLR8 Expression and TLR8-Mediated Inflammatory Responses in Monocytes In Vitro and Experimental Autoimmune Encephalomyelitis In Vivo