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Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis¹

Wen-Qi Lai^2,*, Anastasia Windy Irwan^2,*, Hong Heng Goh^*, Alirio J. Melendez^*,, Iain B. McInnes and Bernard P. Leung^3,*,

^* Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom

Sphingosine kinase (SphK) phosphorylates sphingosine into sphingosine-1-phosphate (S1P). S1P plays a critical role in angiogenesis, inflammation, and various pathologic conditions. To date, two mammalian isoenzymes, SphK1 and SphK2, have been identified. Although both SphK1 and SphK2 share overall homology and produce the common product, S1P, it has been proposed they display different unique and separate functions. In this study, we examined the role of SphK1 and SphK2 in a murine collagen-induced arthritis model by down-regulating each isoenzyme via specific small interfering RNA (siRNA). Prophylactic i.p. administration of SphK1 siRNA significantly reduced the incidence, disease severity, and articular inflammation compared with control siRNA recipients. Treatment of SphK1 siRNA also down-regulated serum levels of S1P, IL-6, TNF-, IFN-, and IgG2a anti-collagen Ab. Ex vivo analysis demonstrated significant suppression of collagen-specific proinflammatory/Th1 cytokine (IL-6, TNF-, IFN-) release in SphK siRNA-treated mice. Interestingly, mice received with SphK2 siRNA develop more aggressive disease; higher serum levels of IL-6, TNF-, and IFN-; and proinflammatory cytokine production to collagen in vitro when compared with control siRNA recipients. Together, these results demonstrate the distinct immunomodulatory roles of SphK1 and SphK2 in the development of inflammatory arthritis by regulating the release of proinflammatory cytokines and T cell responses. These findings raise the possibility that drugs which specifically target SphK1 activity may play a beneficial role in the treatment of inflammatory arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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, 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. E-mail address: phslplb{at}nus.edu.sg

⁴ Abbreviations used in this paper: S1P, sphingosine-1-phosphate; SphK, sphingosine kinase; siRNA, small interfering RNA; IBD, inflammatory bowel disease; RA, rheumatoid arthritis; FLS, fibroblast-like synoviocytes; DMS, N,N-dimethylsphingosine; CIA, collagen-induced arthritis; CII, type II collagen.