title: Dissecting Ascaris glycosphingolipids for immunomodulatory moieties--the use of synthetic structural glycosphingolipid analogues.
abstract: We have previously shown glycosphingolipids of Ascaris suum to have phosphorylcholine (PC) and non-PC immunomodulatory moieties. In the present study we further investigated the nature of the immunomodulatory moieties by employing three synthetic glycosphingolipids each possessing features of the original molecule to examine effects on macrophage and dendritic cell (DC) cytokine production and surface co-stimulatory molecule expression. Compound 2, which lacked PC but contained ceramide, had no effect on either macrophages or DCs. Surprisingly however, Compound 1, which contained PC and hence arguably most resembled the native material, had, with the exception of a small increase in surface antigen expression, no immunomodulatory properties. Conversely, Compound 3, which contained PC but was otherwise least like the native molecule, demonstrated a number of effects on both macrophages and DCs, including induction of Th-1/pro-inflammatory cytokines, inhibition of such cytokines induced by IFN-gamma/LPS and increased expression of co-stimulatory molecules. Taken together these results indicate: (i) that although PC is an immunomodulatory component of the native molecule other structural feature are necessary to allow it to act; (ii) that carbohydrate rather than ceramide is likely to represent a non-PC immunomodulatory moiety; and (iii) that synthetic PC-containing molecules have the potential to act as immunomodulatory drugs.
authors.affiliation: Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: D E
authors.initials: DE
authors.lastname: Kean
authors.forename: I
authors.initials: I
authors.lastname: Ohtsuka
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: N
authors.initials: N
authors.lastname: Hada
authors.forename: T
authors.initials: T
authors.lastname: Takeda
authors.forename: G
authors.initials: G
authors.lastname: Lochnit
authors.forename: R
authors.initials: R
authors.lastname: Geyer
authors.forename: M M
authors.initials: MM
authors.lastname: Harnett
authors.forename: W
authors.initials: W
authors.lastname: Harnett
mesh_terms: D000818:Animals; D017165:Ascaris suum / Q000737:chemistry / Q000276:immunology*; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002518:Ceramides / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006028:Glycosphingolipids / Q000276:immunology* / Q000494:pharmacology; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D053762:Interleukin-12 Subunit p40; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010767:Phosphorylcholine / Q000276:immunology; D021122:Protein Subunits / Q000096:biosynthesis / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D002518:Ceramides; D006028:Glycosphingolipids; D007155:Immunologic Factors; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D010767:Phosphorylcholine; D018664:Interleukin-12