Abstract
Sphingosine analogues display immunosuppressive activities and thus have therapeutic potential in the treatment of autoimmune diseases. In this study, we investigated the effects of the sphingosine analogue AAL-R (FTY720 derivative) on dendritic cell (DC) response upon TLR stimulation. Unlike its known immunosuppressive activity, AAL-R increased TLR7-mediated DC responses by elevating the levels of MHC class I and costimulatory molecules and type I IFN expression and by enhancing the capacity of DCs to induce CD8(+) T cell proliferation. Importantly, the stimulatory activity of AAL-R was dependent on type I IFN signaling, as type I IFN receptor-deficient DCs failed to respond to AAL-R. Also, AAL-R activated p38 MAPK to increase type I IFN synthesis and TLR7-mediated DC maturation. These findings enhance our understanding of sphingosine regulation of the host immune system, in particular upon pathogenic infections.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Fingolimod Hydrochloride
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Humans
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Immunologic Factors / pharmacology*
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Interferon Type I / physiology*
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Phosphorylation / drug effects
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Phosphorylation / immunology
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Propylene Glycols / pharmacology*
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Toll-Like Receptor 7 / physiology*
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Up-Regulation / drug effects
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Up-Regulation / immunology*
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p38 Mitogen-Activated Protein Kinases / metabolism
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p38 Mitogen-Activated Protein Kinases / physiology*
Substances
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Immunologic Factors
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Interferon Type I
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Membrane Glycoproteins
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Propylene Glycols
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Tlr7 protein, mouse
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Toll-Like Receptor 7
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p38 Mitogen-Activated Protein Kinases
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Fingolimod Hydrochloride
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Sphingosine