Volume 6 Supplement 1

24th European Workshop for Rheumatology Research

Open Access

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

  • D Magne1,
  • F Mezin1,
  • G Palmer1 and
  • PA Guerne1
Arthritis Res Ther20046(Suppl 1):61

https://doi.org/10.1186/ar1103

Received: 16 January 2004

Published: 24 February 2004

Background

Leflunomide is an immunomodulatory agent used for the treatment of rheumatoid arthritis (RA) and is known to inhibit the proliferation of several cell types, including T lymphocytes.

Objectives

Because pannus formation due to excessive synoviocyte proliferation is generally associated with the development of RA, we sought to determine the effects of A77-1726, the active metabolite of leflunomide, on synovial fibroblast proliferation.

Methods

Cell viability was investigated by measuring at 490 nm the formation of formazan from MTS tetrazolium, and cell proliferation by determination of thymidine incorporation and cell counts.

Results

Whereas A77-1726 alone had no significant effects on proliferation, it dramatically increased the mitogenic effects of IL-1β. Then we investigated the possible mechanisms of this effect of A77-1726 (i.e. inhibition of DHODH, of tyrosine kinases and COX). The effect was not mediated through inhibition of DHODH because it was not reversed by addition of exogenous uridine. It was not due to inhibition of tyrosine kinases either, because the broad-range inhibitor genistein and the src tyrosine kinase inhibitor PP1 blocked rather than increased IL-1β effects. Finally, although in the absence of IL-1β PGE2 dose-dependently decreased proliferation, it had no effect in the presence of IL-1β, and treatment with indomethacin did not consistently reproduce the effects of A77-1726.

Conclusions

The mitogenic effects of A77-1726 in presence of IL-1β may thus be independent on DHODH and tyrosine kinase inhibition, whereas the role of COX is more uncertain; identification of involved mechanisms may prove useful for the development of related compounds or new therapeutic strategies.

Declarations

Acknowledgement

This work was supported by the Swiss National Science Foundation (grant 3100-064123.00/1 to PAG) and by Aventis Pharma (Frankfurt am Main, Germany).

Authors’ Affiliations

(1)
Department of Pathology, University of Geneva School of Medicine

Copyright

© The Author(s) 2004

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