Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis

Lai, W.-Q., Irwan, A. W., Goh, H. H., Howe, H. S., Yu, D. T., Valle-Onate, R., McInnes, I. B. , Melendez, A. J. and Leung, B. P. (2008) Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis. Journal of Immunology, 181(11), pp. 8010-8017. (doi:10.4049/jimmunol.181.11.8010) (PMID:19017993)

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Publisher's URL: http://www.jimmunol.org/content/181/11/8010.full

Abstract

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-α, 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-α, IFN-γ, 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Leung, Dr Bernard
Authors: Lai, W.-Q., Irwan, A. W., Goh, H. H., Howe, H. S., Yu, D. T., Valle-Onate, R., McInnes, I. B., Melendez, A. J., and Leung, B. P.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Immunology
Publisher:American Association of Immunologists
ISSN:0022-1767
ISSN (Online):1550-6606

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
462311Therapeutic potential of Sphingosine Kinase blockage in allergic anaphylaxis.Alirio Melendez RomeroMedical Research Council (MRC)G0700794Institute of Infection Immunity and Inflammation