Chemical Hypoxia Brings to Light Altered Autocrine Sphingosine-1-Phosphate Signalling in Rheumatoid Arthritis Synovial Fibroblasts.

Chenqi Zhao,Mohamed Touaibia,Sylvain G Bourgoin,Maria J Fernandes,John A Di Battista,Uriel Moreno-Nieves

doi:10.1155/2015/436525

Abstract

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.

Highlights

Rheumatoid arthritis (RA) is a chronic systemic disorder that causes destruction of joints through inflammation and proliferation of the synovial membrane [1, 2]
We report that the blockade of S1P2 or S1P3 receptors attenuates CoCl2-mediated IL-8 and monocyte chemotactic protein-1 (MCP-1) secretion in normal fibroblast-like synoviocytes (FLS) but not in RAFLS
Small amounts of IL-8 (

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic systemic disorder that causes destruction of joints through inflammation and proliferation of the synovial membrane [1, 2]. 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] This 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]. The 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].

Methods

Results

Conclusion