Patients with early rheumatoid arthritis (RA) have high expression of toll-like receptors (TLRs) 3 and 4, say Swiss scientists who believe their findings indicate that the signaling pathway is involved in the disease process.
Recent studies have shown that RA synovial fibroblasts (RASFs), which take an active part in the inflammatory and matrix-degrading processes of RA, are stimulated by TLR pathway activation.
To investigate further, Fabia Brentano, from University Hospital Zurich, and colleagues studied 11 patients with longstanding RA (average 21.8 years, 10 with early RA (average 0.4 years), and 11 with osteoarthritis.
Polymerase chain reaction was used to analyse TLR 1–10 expression in RASFs, osteoarthritis synovial fibroblasts (OASFs), and skin fibroblasts, and fibroblasts were stimulated with tumor necrosis factor alpha, interleukin (IL)-1beta, bacterial lipopeptide, the TLR-3 ligand poly(I-C), lipopolysaccharaide, and flagellin. The team also assessed IL-6 production and induction of TLRs 2–5, and matrix metalloproteinases (MMPs) 3 and 13 messenger RNA.
The results, published in the journal Arthritis and Rheumatism, indicate that TLR1–6, but not TLR1–10, were expressed by RASFs, OASFs, normal synovial fibroblasts, and skin fibroblasts, with the highest expression found for TLR-3, followed by TLR-4. There were no significant differences in expression between cell types.
In addition, the team found that stimulation of synovial fibroblasts by poly(I-C) led to the most substantial increases in IL-6, MMP-3, and MMP-13 expression. However, none of the tests stimuli had any impact on regulation of MMP-3 or MMP-13 in skin fibroblasts.
Both TLR-3 and TLR-4 were highly expressed in synovial tissues from early RA patients at levels comparable to those in patients with longstanding RA. In both sets of RA patients, levels of expression were increased compared with osteoarthritis patients.
The team conclude: “Our data suggest that stimulation of TLR pathways occurs early in RA, resulting in the activation of synovial fibroblasts and contributing to the development of synovial inflammation and joint destruction.”