Magne D, Mézin F, Palmer G, Guerne P-A
Division of Rheumatology, University Hospital, Geneva, Switzerland.
Inflamm Res. 2006 Nov;55(11):469-75. doi: 10.1007/s00011-006-5196-x.
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.
Human SFs were used. Cell proliferation was investigated using MTS assay, by (3)H-thymidine incorporation and cell counts.
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.
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.
滑膜成纤维细胞（SF）过度增殖在类风湿性关节炎中具有损害作用。因此，我们试图确定来氟米特的活性代谢产物A77 1726对SF增殖的影响。
使用人SF。通过MTS测定、³H-胸腺嘧啶核苷掺入和细胞计数研究细胞增殖。
虽然单独的A77 1726没有作用，但它显著增强了白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的促有丝分裂作用。环氧化酶抑制可能至少部分参与其中，因为吲哚美辛表现出类似的作用，并且前列腺素E2抑制SF增殖。相反，A77 1726的作用似乎不是通过嘧啶池的消耗或酪氨酸激酶抑制介导的。
A77 1726在存在IL-1β和TNF-α的情况下显示出增殖作用。进一步阐明相关机制可能对来氟米特的应用、相关化合物的开发或新治疗策略的制定有用。
