Abstract.
Objective and design
Excessive synovial fibroblast (SF) proliferation is detrimental in rheumatoid arthritis. We therefore sought to determine the effects of A77 1726, the active metabolite of leflunomide, on SF proliferation.
Methods
Human SFs were used. Cell proliferation was investigated using MTS assay, by 3H-thymidine incorporation and cell counts.
Results
Whereas A77 1726 alone had no effects, it significantly increased the mitogenic effects of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Cyclooxygenase inhibition might be at least partly involved, since indomethacin displayed similar effects, and since prostaglandin E2 inhibited SF proliferation. In contrast, the effect of A77 1726 did not appear to be mediated through depletion of the pyrimidine pool or inhibition of tyrosine kinases.
Conclusion
A77 1726 displays proliferative effects in presence of IL-1β and TNF-α. Further elucidation of involved mechanisms may prove useful for the utilization of leflunomide, the development of related compounds or elaboration of new therapeutic strategies.
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Abbreviations
- COX:
-
cyclooxygenase
- DHODH:
-
dihydroorotate dehydrogenase
- DMARD:
-
disease-modifying anti-rheumatic drug
- IL-1β:
-
interleukin-1β
- OA:
-
osteoarthritis
- PGE2:
-
prostaglandin E2
- RA:
-
rheumatoid arthritis
- SF:
-
synovial fibroblast
- TNF-α:
-
tumor necrosis factor-α.
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This work was supported by Aventis Pharma (Frankfurt am Main, Germany).
Received 6 December 2005; returned for revision 30 May 2006; accepted by J. Di Battista 3 June 2006
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Magne, D., Mézin, F., Palmer, G. et al. The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1β and TNF-α. Inflamm. res. 55, 469–475 (2006). https://doi.org/10.1007/s00011-006-5196-x
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DOI: https://doi.org/10.1007/s00011-006-5196-x