Inflammation Research

, Volume 55, Issue 11, pp 469–475

The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1β and TNF-α

Original Research Paper

DOI: 10.1007/s00011-006-5196-x

Cite this article as:
Magne, D., Mézin, F., Palmer, G. et al. Inflamm. res. (2006) 55: 469. doi:10.1007/s00011-006-5196-x

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.

Key words.

Leflunomide Rheumatoid arthritis Synovial fibroblast Proliferation Cyclooxygenase 

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.

Copyright information

© Birkhäuser Verlag, Basel 2006

Authors and Affiliations

  • D. Magne
    • 1
    • 2
    • 3
  • F. Mézin
    • 1
    • 2
  • G. Palmer
    • 1
    • 2
  • P. -A. Guerne
    • 1
    • 2
  1. 1.Division of RheumatologyUniversity HospitalGenevaSwitzerland
  2. 2.Department of Pathology and ImmunologyUniversity of Geneva School of MedicineGenevaSwitzerland
  3. 3.Biomaterials and BiotechnologiesBoulogne/merFrance

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