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

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.