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Effects of leflunomide on interleukin-1 receptor antagonist (IL-1Ra) synthesis in chondrocytes and synovial fibroblasts
Arthritis Res Ther volume 5, Article number: 55 (2003)
We analyzed the effects of the active metabolite of leflunomide, A77-1726, on IL-1Ra production by chondrocytes and synovial fibroblasts, with regards to the relevance of its use in RA and other cartilage damaging diseases.
Methods and results
Cartilage was obtained from joints replaced for osteoarthritis or broken femoral neck. Synovial membranes were obtained from joints replaced for osteoarthritis. Cells were isolated by collagenase digestion; chondrocytes were used either directly (primary cells) or between passages 1 and 5 (dedifferentiated cells). IL-1Ra concentrations in cell conditioned media (CM) or cell lysates were assessed using a sandwich ELISA. In chondrocytes and synoviocytes, A77-1726 dose-dependently enhanced the stimulatory effects of IL-1β or TNF on IL-1Ra production (average 2 fold increase in primary chondrocytes, 10 fold increase in synoviocytes). A maximal response was observed at 100 μM. In synoviocytes, A77-1726 increased the production of soluble (s; as measured in CM) and intracellular (ic; as measured in cell lysates) IL-1Ra; in contrast, no significant amounts of icIL-1Ra were recovered from primary chondrocytes. We next investigated putative pathways involved, first focusing on known effects of A77-1726 on uridine and prostaglandin E2 (PGE2) synthesis. The addition of exogenous uridine did not modify the effects of A77-1726. The addition of PGE2 partially reversed the effects of A77-1726 in chondrocytes and synoviocytes. Indomethacin also increased IL-1Ra production, although less potently than A77-1726, and its effects were completely annulled by low doses of PGE2. A77-1726 at 100 μM inhibited by 95–98% the production of PGE2 induced by IL-1β and TNF-α; this was not significantly different from the inhibition achieved by optimal doses of indomethacin.
A77-1726 may thus possess chondroprotective effects by increasing IL-1Ra release by chondrocytes and synoviocytes. The effects of A77-1726 seem to arise partially through inhibition of PGE2 synthesis, but other mechanisms likely concur to its stimulatory effect on IL-1Ra production.
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Cite this article
Palmer, G., Burger, D., Mezin, F. et al. Effects of leflunomide on interleukin-1 receptor antagonist (IL-1Ra) synthesis in chondrocytes and synovial fibroblasts. Arthritis Res Ther 5, 55 (2003) doi:10.1186/ar685
- Conditioned Medium