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Chemical Hypoxia Brings to Light Altered Autocrine Sphingosine-1-Phosphate
Signalling in Rheumatoid Arthritis Synovial Fibroblasts
#MMPMID26556954
Zhao C
; Moreno-Nieves U
; Di Battista JA
; Fernandes MJ
; Touaibia M
; Bourgoin SG
Mediators Inflamm
2015[]; 2015
(?): 436525
PMID26556954
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Emerging evidence suggests a role for sphingosine-1-phosphate (S1P) in various
aspects of rheumatoid arthritis (RA) pathogenesis. In this study we compared the
effect of chemical hypoxia induced by cobalt chloride (CoCl2) on the expression
of S1P metabolic enzymes and cytokine/chemokine secretion in normal
fibroblast-like synoviocytes (FLS) and RAFLS. RAFLS incubated with CoCl2, but not
S1P, produced less IL-8 and MCP-1 than normal FLS. Furthermore, incubation with
the S1P2 and S1P3 receptor antagonists, JTE-013 and CAY10444, reduced
CoCl2-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 CoCl2 decreased SGPP1
mRNA and protein and SPL mRNA as well. Inhibition of SPL enhanced CoCl2-mediated
cytokine/chemokine release and restored autocrine activation of S1P2 and S1P3
receptors in RAFLS. The results suggest that the sphingolipid pathway regulating
the intracellular levels of S1P is dysregulated in RAFLS and has a significant
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 inflammation.
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