title: Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions.
abstract: Sphingolipids are a class of biologically active lipids that have a role in multiple biological processes including inflammation. Sphingolipids exert their functions by direct signaling or through signaling by their specific receptors. Phosphorylated FTY720 (FTY720P) is a sphingosine 1-phosphate (S1P) analogue that is currently in trial for treatment of multiple sclerosis (MS), which targets all S1P receptors but S1P(2). To date, however, it remains unknown whether FTY720P may exert direct anti-inflammatory effects within the central nervous system (CNS), because data concerning S1P receptor expression and regulation under pathological conditions in the human brain are lacking. To investigate potential regulation of S1P receptors in the human brain during MS, we performed immunohistochemical analysis of S1P receptor 1 and 3 expression in well-characterized MS lesions. A strong increase in S1P receptor 1 and 3 expression on reactive astrocytes was detected in active and chronic inactive MS lesions. In addition, we treated primary cultures of human astrocytes with the proinflammatory cytokine tumor necrosis factor-alpha to identify the regulation of S1P(1/3) on astrocytes under pathological conditions. Importantly, we demonstrate that FTY720P exerts an anti-inflammatory action on human astrocytes by limiting secretion of proinflammatory cytokines. Our data demonstrate that reactive astrocytes in MS lesions and cultured under proinflammatory conditions strongly enhance expression of S1P receptors 1 and 3. Results from this study indicate that astrocytes may act as a yet-unknown target within the CNS for the anti-inflammatory effects observed after FTY720P administration in the treatment of MS.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Van Doorn
authors.forename: Jack
authors.initials: J
authors.lastname: Van Horssen
authors.forename: Dennis
authors.initials: D
authors.lastname: Verzijl
authors.forename: Maarten
authors.initials: M
authors.lastname: Witte
authors.forename: Eric
authors.initials: E
authors.lastname: Ronken
authors.forename: Bert
authors.initials: B
authors.lastname: Van Het Hof
authors.forename: Kim
authors.initials: K
authors.lastname: Lakeman
authors.forename: Christine D
authors.initials: CD
authors.lastname: Dijkstra
authors.forename: Paul
authors.initials: P
authors.lastname: Van Der Valk
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Alewijnse
authors.forename: Stephan L M
authors.initials: SL
authors.lastname: Peters
authors.forename: Helga E
authors.initials: HE
authors.lastname: De Vries
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000503:physiopathology*; D011409:Propylene Glycols / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018925:Chemokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine