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Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions.
Glia. 2010 Sep; 58(12):1465-76.GLIA

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+Show Affiliations

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20648639

Citation

Van Doorn, Ruben, et al. "Sphingosine 1-phosphate Receptor 1 and 3 Are Upregulated in Multiple Sclerosis Lesions." Glia, vol. 58, no. 12, 2010, pp. 1465-76.
Van Doorn R, Van Horssen J, Verzijl D, et al. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia. 2010;58(12):1465-76.
Van Doorn, R., Van Horssen, J., Verzijl, D., Witte, M., Ronken, E., Van Het Hof, B., Lakeman, K., Dijkstra, C. D., Van Der Valk, P., Reijerkerk, A., Alewijnse, A. E., Peters, S. L., & De Vries, H. E. (2010). Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia, 58(12), 1465-76. https://doi.org/10.1002/glia.21021
Van Doorn R, et al. Sphingosine 1-phosphate Receptor 1 and 3 Are Upregulated in Multiple Sclerosis Lesions. Glia. 2010;58(12):1465-76. PubMed PMID: 20648639.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. AU - Van Doorn,Ruben, AU - Van Horssen,Jack, AU - Verzijl,Dennis, AU - Witte,Maarten, AU - Ronken,Eric, AU - Van Het Hof,Bert, AU - Lakeman,Kim, AU - Dijkstra,Christine D, AU - Van Der Valk,Paul, AU - Reijerkerk,Arie, AU - Alewijnse,Astrid E, AU - Peters,Stephan L M, AU - De Vries,Helga E, PY - 2010/7/22/entrez PY - 2010/7/22/pubmed PY - 2010/11/5/medline SP - 1465 EP - 76 JF - Glia JO - Glia VL - 58 IS - 12 N2 - 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. SN - 1098-1136 UR - https://www.unboundmedicine.com/medline/citation/20648639/Sphingosine_1_phosphate_receptor_1_and_3_are_upregulated_in_multiple_sclerosis_lesions_ L2 - https://doi.org/10.1002/glia.21021 DB - PRIME DP - Unbound Medicine ER -