Abstract
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) 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)2D3 is in part mediated through an interplay between 1,25(OH)2D3 and toll-like receptor (TLR)7/8 signaling. 1,25(OH)2D3 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)2D3. To determine the molecular mechanism by which 1,25(OH)2D3 suppresses EAE induction of TLR8 and inflammatory cytokine expression, we evaluated whether 1,25(OH)2D3 can directly inhibit TLR8 signaling and the resulting inflammatory responses in human THP-1 monocytes. 1,25(OH)2D3 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)2D3 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)2D3 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)2D3 and may mediate the anti-inflammatory action of 1,25(OH)2D3. Our findings also point to a destructive role of TLR8 in EAE and shed lights on pathogenesis of multiple sclerosis.
Highlights
Multiple sclerosis (MS) is a debilitating disease of the central nerve system (CNS) which affects more than 2.5 million people worldwide every year [1]
Figure 5. 1,25(OH)2D3 inhibits TLR8-mediated inflammatory cytokine expression in human THP-1 monocytes. (A–B) Human monocyte THP-1 cells were pretreated with 1,25(OH)2D3 (100 nM) for 30 min and stimulated with CL075 (1 mg/ml) or ssRNA (5 mg/ml) for 20 h. (C–D) THP1 cells were pretreated with different doses of 1,25(OH)2D3 (0.1–200 nM) for 30 min and incubated with CL075 (1 mg/ml) for additional 20 h
The murine TLR8 was once suggested to be biologically inactive based on the finding that viral ssRNA, the natural ligand for human TLR7/8, failed to activate mouse TLR8 [31]
Summary
Multiple sclerosis (MS) is a debilitating disease of the central nerve system (CNS) which affects more than 2.5 million people worldwide every year [1]. Current therapies use mostly disease-modifying drugs, focusing on blocking and regulating systemic functions and CNS infiltration of immune cells [3], [4]. These therapies only attenuate or delay MS symptoms and are not effective in halting the disease progression [3], [4]. Similar to what occurs in MS, excessive production of inflammatory cytokines by activated microglia and invading inflammatory cells appear to play a critical role [1], [5]. Identification of the molecules which mediate the anti-immune/inflammatory action of 1,25(OH)2D3 may uncover new mechanisms by which this hormone inhibits inflammatory cytokine production
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