Anti-inflammatory effects of sphingosine kinase modulation in inflammatory arthritis.
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, S1P(1) receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P(1) enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E(2) 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-alpha, IL-6, IL-1beta, 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-alpha, IFN-gamma, 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.
Lai
Wen-Qi
WQ
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
Irwan
Anastasia Windy
AW
Goh
Hong Heng
HH
Howe
Hwee Siew
HS
Yu
David T
DT
Valle-Oñate
Rafael
R
McInnes
Iain B
IB
Melendez
Alirio J
AJ
Leung
Bernard P
BP
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D024043:Collagen Type II / Q000276:immunology / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008246:Lysophospholipids / Q000276:immunology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D018919:Neovascularization, Physiologic / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000276:immunology; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D013582:Synovial Fluid / Q000201:enzymology / Q000276:immunology*; D020298:U937 Cells; D000099157:Sphingosine Kinase
D024043:Collagen Type II; D051546:Cyclooxygenase 2; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D008246:Lysophospholipids; D020780:Matrix Metalloproteinase 9; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C496540:PTGS2 protein, human; C061800:N,N-dimethylsphingosine