Distinct roles of sphingosine kinase 1 and 2 in murine collagen-induced arthritis

Lai, W.-Q., Irwan, A. W., Goh, H. H., Melendez, A. J., McInnes, I. B. and Leung, B. P. (2009) Distinct roles of sphingosine kinase 1 and 2 in murine collagen-induced arthritis. Journal of Immunology, 183(3), pp. 2097-2103. (doi:10.4049/jimmunol.0804376) (PMID:19596980)

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Abstract

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-α, IFN-γ, and IgG2a anti-collagen Ab. Ex vivo analysis demonstrated significant suppression of collagen-specific proinflammatory/Th1 cytokine (IL-6, TNF-α, IFN-γ) release in SphK siRNA-treated mice. Interestingly, mice received with SphK2 siRNA develop more aggressive disease; higher serum levels of IL-6, TNF-α, and IFN-γ; 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.

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., Melendez, A. J., McInnes, I. B., 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
Journal Abbr.:J. Immunol.
Publisher:American Association of Immunologists
ISSN:0022-1767
ISSN (Online):1550-6606
Published Online:13 July 2009

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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