Research Article Chemical Hypoxia Brings to Light Altered Autocrine Sphingosine-1-Phosphate Signalling in Rheumatoid Arthritis Synovial Fibroblasts Chenqi Zhao, 1 Uriel Moreno-Nieves, 1 John A. Di Battista, 2 Maria J. Fernandes, 1 Mohamed Touaibia, 3 and Sylvain G. Bourgoin 1 1 Division of Infectious Diseases and Immunology, CHU de Quebec Research Center and Faculty of Medicine, Laval University, Quebec, QC, Canada G1V 4G2 2 Division of Rheumatology and Clinical Immunology, Royal Victoria Hospital, McGill University, Montreal, QC, Canada H3A 1A1 3 Department of Chemistry and Biochemistry, University of Moncton, Moncton, NB, Canada E1A 3E9 Correspondence should be addressed to Sylvain G. Bourgoin; sylvain.bourgoin@crchul.ulaval.ca Received 15 July 2015; Accepted 26 August 2015 Academic Editor: Laura Riboni Copyright © 2015 Chenqi Zhao et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Emerging evidence suggests a role for sphingosine-1-phosphate (S1P) in various aspects of rheumatoid arthritis (RA) pathogenesis. In this study we compared the efect of chemical hypoxia induced by cobalt chloride (CoCl 2 ) on the expression of S1P metabolic enzymes and cytokine/chemokine secretion in normal ibroblast-like synoviocytes (FLS) and RAFLS. RAFLS incubated with CoCl 2 , but not S1P, produced less IL-8 and MCP-1 than normal FLS. Furthermore, incubation with the S1P 2 and S1P 3 receptor antagonists, JTE-013 and CAY10444, reduced CoCl 2 -mediated chemokine production in normal FLS but not in RAFLS. RAFLS showed lower levels of intracellular S1P and enhanced mRNA expression of S1P phosphatase 1 (SGPP1) and S1P lyase (SPL), the enzymes that are involved in intracellular S1P degradation, when compared to normal FLS. Incubation with CoCl 2 decreased SGPP1 mRNA and protein and SPL mRNA as well. Inhibition of SPL enhanced CoCl 2 -mediated cytokine/chemokine release and restored autocrine activation of S1P 2 and S1P 3 receptors in RAFLS. he results suggest that the sphingolipid pathway regulating the intracellular levels of S1P is dysregulated in RAFLS and has a signiicant impact on cell autocrine activation by S1P. Altered sphingolipid metabolism in FLS from patients with advanced RA raises the issue of synovial cell burnout due to chronic inlammation. 1. Introduction Rheumatoid arthritis (RA) is a chronic systemic disorder that causes destruction of joints through inlammation and proliferation of the synovial membrane [1, 2]. In RA, the syn- ovial tissue lining the joints becomes inlamed. In comparison with the normal synovial membrane, which is normally 1-2 cell layers thick, RA synovial tissue is hypertrophic and invaded by an excess of various leukocytes including neutrophils, T cells, macrophages, and monocytes [3]. his recruitment of leukocytes is likely to be mediated by selective chemotactic factors, such as interleukin-8 (IL-8) that recruits neutrophils and T cells, and monocyte chemotactic protein-1 (MCP-1) that recruits monocytes, into the synovium [4, 5]. A role for IL-8 [6, 7] and MCP-1 [8, 9] in these processes has been highlighted. he synthesis of chemokines in RA may be dependent, at least in part, on the production of inlammatory cytokines, such as IL-1 and tumor necrosis factor- (TNF-) [4], by the hypertrophic synovium and activated leukocytes. he complex cascade of production of chemokines, cytokines, and tissue-remodelling enzymes associated with leukocyte recruitment plays a role in synovial cell proliferation and joint erosion in RA [1, 2, 10]. Eventually, the thickened synovial membrane decreases capillary density and the oxygen tension in the joint [11–13]. Severe reduction of mean oxygen pressure in the RA synovium compared to that of healthy joints correlates with severity of inlammation [14–16]. he hypoxic RA joint environment in turn afects Hindawi Publishing Corporation Mediators of Inflammation Volume 2015, Article ID 436525, 12 pages http://dx.doi.org/10.1155/2015/436525