title: The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha.
abstract: OBJECTIVE
  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 (3)H-thymidine incorporation and cell counts.
  
  
  RESULTS
  Whereas A77 1726 alone had no effects, it significantly increased the mitogenic effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). 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.
  
  
  CONCLUSIONS
  A77 1726 displays proliferative effects in presence of IL-1beta and TNF-alpha. Further elucidation of involved mechanisms may prove useful for the utilization of leflunomide, the development of related compounds or elaboration of new therapeutic strategies.
authors.affiliation: Division of Rheumatology, University Hospital, Geneva, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Magne
authors.forename: F
authors.initials: F
authors.lastname: Mézin
authors.forename: G
authors.initials: G
authors.lastname: Palmer
authors.forename: P-A
authors.initials: PA
authors.lastname: Guerne
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003437:Crotonates; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000502:physiology; D007555:Isoxazoles / Q000378:metabolism / Q000627:therapeutic use; D019169:Jurkat Cells / Q000187:drug effects / Q000473:pathology; D000077339:Leflunomide; D009570:Nitriles; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D014052:Toluidines; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014529:Uridine / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003437:Crotonates; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D053583:Interleukin-1beta; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; D014409:Tumor Necrosis Factor-alpha; C527525:teriflunomide; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D000077339:Leflunomide; D014529:Uridine