Abstract
Rheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation and polyarthritis. Inflammatory mediators activate fibroblast-like synovial cells which exhibit very unique characteristics in the process of bone resorption. The rheumatoid synoviocytes produce high levels of prostaglandin E2 (PGE2) production through increased cyclooxygenase (COX)-2 expression. PGE2 is thought to be a major PG species working in RA pathogenesis and PGE2 exhibits various biological actions: for example, PGE2 mediates some inflammatory responses and bone resorption as well as activation of osteoclasts. Prostaglandin E synthase (PGES) is an enzyme that acts downstream of COX-2 and catalyzes the final step of PGE2 biosynthesis. Microsomal PGES (mPGES)-1 shows the coordinated induction with COX-2 under inflammatory conditions. Sphigosine-1-phosphate (S1P) is the final metabolite of the sphingolipid pathway and controls a wide variety of essential cellular processes. S1P is involved in various pathologic conditions and has been implicated as an important mediator in angiogenesis, cancer, and autoimmune diseases such as RA. S1P1 receptor is strongly expressed in RA synovium, and S1P enhances inflammatory cytokine-induced COX-2 expression and PGE2 production. FTY720 (fingolimod) is a high-affinity agonist for S1P receptors and induces internalization of the receptors. FTY720 has been shown to be a useful agent for the prevention of transplant rejection and autoimmune diseases such as multiple sclerosis and RA. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. PPARγ is activated by a range of synthetic and naturally occurring substances, including anti-diabetic thiazolidinediones such as troglitazone and 15-deoxy-Δ12-14-PGJ2 (15d-PGJ2). PPARγ ligands suppress arthritis in Lewis rats with adjuvant- induced arthritis, and induce rheumatoid synoviocye apoptosis. This mini-review focuses on the role of lipid mediators in the pathogenesis of RA.
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