title: Sphingosine analogue AAL-R increases TLR7-mediated dendritic cell responses via p38 and type I IFN signaling pathways.
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.
authors.affiliation: Department of Surgery, University of Missouri-Columbia, Columbia, MO 65212, USA.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Seo
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Pritzl
authors.forename: Madhuvanthi
authors.initials: M
authors.lastname: Vijayan
authors.forename: Celeste R
authors.initials: CR
authors.lastname: Blake
authors.forename: Mariah E
authors.initials: ME
authors.lastname: McClain
authors.forename: Bumsuk
authors.initials: B
authors.lastname: Hahm
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007370:Interferon Type I / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011409:Propylene Glycols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D007155:Immunologic Factors; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D011409:Propylene Glycols; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D048051:p38 Mitogen-Activated Protein Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine