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Inflammation & Allergy - Drug Targets (Discontinued)


ISSN (Print): 1871-5281
ISSN (Online): 2212-4055

Impact of Sphingosine Kinase on Inflammatory Pathways in Fibroblast-Like Synoviocytes

Author(s): DeAnna A. Baker, Lina M. Obeid and Gary S. Gilkeson

Volume 10, Issue 6, 2011

Page: [464 - 471] Pages: 8

DOI: 10.2174/187152811798104863

Price: $65


Sphingolipids are mediators of inflammation; changes in their cellular concentration modulate specific cellular functions. Investigations of sphingosine kinases (SphK) and sphingosine 1 phosphate (S1P) in TNFα driven murine models of rheumatoid arthritis (RA), identified SphK/S1P as important intermediaries in TNFα mediated synovial proinflammatory pathways. Fibroblast-like synoviocytes (FLS) are key contributors to RA pathogenesis and express both SphK 1 and 2. To pinpoint the mechanisms of SphK effects in the inflammatory response of murine FLS in vitro, we derived SphK1 null (SphK1-/-) FLS and SphK1 wild-type (SphK1+/+) FLS from the knee joints of B6 mice. Significantly less MMP1a and IL-6 were produced by mTNFα-stimulated SphK1-/- FLS versus SphK1+/+ FLS. Trends toward less PGE2 as well as activated, ERK 1/2 and STAT3 were present in SphK1-/- FLS versus SphK1+/+ FLS. Thus genetic inhibition of SphK1 activity resulted in decreased expression of inflammatory mediators and decreased activation of inflammatory pathways in TNFα stimulated murine FLS. This decreased inflammatory phenotype in FLS lacking SphK1 activity is consistent with the attenuated TNF-α-driven arthritis in vivo in SphK1 deficient mice and adds to the understanding of the mechanistic role of SpK1/S1P in rheumatoid arthritis. Thus, specific therapeutic can be targeted with SphK inhibitors in rheumatoid arthritis.

Keywords: ERK1/2, inflammation, MMP1a, sphingosine kinase, STAT3, TNFα, Tumor necrosis factor alpha, Sphingolipids, SphK1-/-, (SphK1+/+, Fibroblast-like synoviocytes

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