title: Sphingosylphosphorylcholine inhibits macrophage adhesion to vascular smooth muscle cells.
abstract: Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-α (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease.
authors.affiliation: School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wirrig
authors.affiliation: School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Jenny S
authors.initials: JS
authors.lastname: McKean
authors.affiliation: School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Wilson
authors.affiliation: School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. Electronic address: g.f.nixon@abdn.ac.uk.
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Nixon
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D014409:Tumor Necrosis Factor-alpha; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D013110:Sphingosine
keywords: Lipid raft; Macrophage; Nitric oxide synthase; Sphingolipids; Vascular smooth muscle