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Rheumatology 2003; 42: 89-96
© 2003 British Society for Rheumatology
The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like synoviocytes
Division of Immunology and Allergy, Clinical Immunology Unit (Hans Wilsdorf Laboratory), Department of Internal Medicine, University Hospital, Geneva, Switzerland
Objectives. To investigate the effects of the active metabolite of leflunomide, A77 1726, on fibroblast-like synoviocytes. In rheumatoid arthritis (RA) synoviocytes participate in tissue destruction by producing metalloproteinases (MMP), prostaglandin E2 (PGE2) and interleukin (IL) 6, which are involved in extracellular matrix degradation, resorption of the mineral phase and osteoclast-mediated bone resorption.
Methods. Human synoviocytes were stimulated with IL-1
or tumour necrosis factor (TNF-) in the presence of A77 1726. Culture supernatants were analysed for production of interstitial collagenase (MMP-1), tissue-inhibitor of metalloproteinases 1 (TIMP-1), PGE2 and IL-6. Total RNA was isolated and analysed for steady-state levels of MMP-1, cyclooxygenase-2 (COX-2) and IL-6 mRNA.
Results. A77 1726 inhibited the production of PGE2 in synoviocytes activated by TNF- and IL-1 with median inhibitory concentrations (IC50) of 7 and 3 µM respectively. In contrast, MMP-1 and IL-6 production was inhibited at high A77 1726 concentrations (> 10 µM), whereas TIMP-1 was not affected. The inhibition of MMP-1 and IL-6 production was due to the known inhibitory effect of A77 1726 on pyrimidine synthesis, as it was reversed by the addition of uridine. This did not apply to PGE2 production, which was inhibited via direct action of A77 1726 on COX-2, as shown by the increasing amount of substrate (arachidonic acid) in the culture medium.
Conclusion. This study shows that some of the beneficial effect of leflunomide in RA patients may be due to the inhibition of PGE2, IL-6 and MMP-1 production in synoviocytes. This effect, coupled with its multiple inhibitory effects on T lymphocyte functions, might account for the significant reduction in the rate of disease progression in RA patients treated with leflunomide.
KEY WORDS: Rheumatoid arthritis, PGE2, MMP-1, IL-6, Synoviocytes.
Correspondence to: D. Burger, Clinical Immunology Unit, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail: danielle.burger{at}hcuge.ch
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