title: Sphingosine kinase and sphingosine-1-phosphate receptors: novel therapeutic targets of rheumatoid arthritis?
abstract: Rheumatoid arthritis (RA) is a chronic, destructive, autoimmune joint disease characterized by elevated levels of proinflammatory cytokine production. Sphingosine kinase (SphK) phosphorylates sphingosine into sphingosine-1-phosphate. Synovial fluid of RA patients exhibits significantly higher levels of S1P than their non-inflammatory osteoarthritis counterparts. SphK blockade suppresses cytokines and MMP-9 release in RA peripheral blood mononuclear cells. In addition, downregulation of SphK1 either through a specific siRNA approach or transgenic human TNF-α SphK1-deficient mice (hTNF-α/SphK1(-/-)) exhibit significantly less synovial inflammation and joint pathology. By contrast, SphK2 modulation leads to disease exacerbation. These results clearly demonstrate that such anti- and proinflammatory potential of SphK1/2 modulation may alter the outcome in RA synovitis and raises the possibility that drugs that specifically target SphK1 activity may play a beneficial role in the treatment of RA and other autoimmune rheumatic diseases.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Lai
authors.forename: Faith Li-Ann
authors.initials: FL
authors.lastname: Chia
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D006801:Humans; D058990:Molecular Targeted Therapy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000276:immunology*; D049349:Receptors, Lysosphingolipid / Q000276:immunology*; D000099157:Sphingosine Kinase
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase