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* Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore;
Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore, Republic of Singapore;
Rheumatology Division, University of California, Los Angeles, CA 90095-167022;
Division of Rheumatology, Hospital Militar Central/Universidad de la Sabana, Bogotá, Colombia; and
¶ Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, U.K.
Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P1 receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P1 enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E2 production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-
, IL-6, IL-1β, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-, IFN-
, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines.
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1 This work was supported by the Office of Life Sciences, National University of Singapore. W.-Q.L. is supported by a scholarship from the National University of Singapore, Republic of Singapore.
2 W.-Q.L. and A.W.I. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Bernard P. Leung, Department of Physiology, 2 Medical Drive, MD9, National University of Singapore, Singapore 117597, Republic of Singapore. E-mail address: phslplb{at}nus.edu.sg
4 Abbreviations used in this paper: S1P, sphingosine-1-phosphate; CIA, collagen-induced arthritis; CII, type II collagen; DMS, N,N-dimethylsphingosine; MMP, matrix metalloproteinase; OA, osteoarthritis; PB, peripheral blood; RA, rheumatoid arthritis; siRNA, small interfering RNA; SphK, sphingosine kinase.
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  W.-Q. Lai, A. W. Irwan, H. H. Goh, A. J. Melendez, I. B. McInnes, and B. P. Leung Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis J. Immunol., August 1, 2009; 183(3): 2097 - 2103. [Abstract] [Full Text] [PDF]
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