Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells
Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells
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DOI：
10.4049/jimmunol.179.10.6479
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Tanaka, Yoshiya
中科院分区：
文献类型：
--
作者：
Sawamukai, Norifumi;Saito, Kazuyoshi;Tanaka, Yoshiya
肥大细胞释放许多炎症介质，这些炎症介质不仅在过敏性疾病中起重要作用，而且在慢性炎症性疾病、自身免疫性疾病等中也起重要作用。类风湿关节炎滑膜中存在大量肥大细胞，已知肥大细胞缺陷小鼠不会发生滑膜炎。因此，认为肥大细胞在类风湿性关节炎的发病机制中起着非常重要的作用。来氟米特是临床上用于治疗类风湿性关节炎的药物。我们使用临床剂量的2-氰基-3-羟基-N-（4-三氟甲基苯基）-丁烯酰胺（A77 1726）（来氟米特的活性代谢产物），并以浓度依赖性方式减少了活的人原代肥大细胞的数量。尿苷不能逆转这种下降。不涉及通过二氢乳清酸脱氢酶抑制抑制嘧啶合成，这是A77 1726的主要作用机制。A77 1726可显著诱导人肥大细胞凋亡，并以浓度依赖性方式抑制肥大细胞重要的生存信号Akt的磷酸化。A77 1726也使Akt存活途径的下游分子半胱天冬酶3和9片段化。此外，第一次证明，该结果涉及的机制是PDK 1磷酸化的浓度依赖性抑制，其控制Akt的活化。这些结果表明了一种新的控制肥大细胞的方法，因此可能是治疗与肥大细胞相关的各种疾病的创新方法的基础。
Mast cells release many inflammatory mediators that play an important role not only in allergic diseases but also in chronic inflammatory diseases, autoimmune diseases, and others. A lot of mast cells exist in synovium of rheumatoid arthritis, and it is known that synovitis does not occur in mast cell-deficient mice. Thus, it is thought that mast cells play a very important role in rheumatoid arthritis pathogenesis. Leflunomide is a drug used clinically in the treatment of rheumatoid arthritis. We used clinical doses of 2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-butenamide (A77 1726), which is an active metabolite of leflunomide, and decreased the number of viable human primary mast cells in a concentration-dependent manner. This decrease was not reversed by uridine. Inhibition of pyrimidine synthesis by dihydro-orotic acid dehydrogenase inhibition, which is the primary mechanism of action of A77 1726, was not involved. A77 1726 dramatically induced apoptosis of human mast cells and inhibited the phosphorylation of Akt, an important survival signal of mast cells, in a concentration-dependent manner. Caspases 3 and 9, downstream molecules of Akt survival pathway, were also fragmented by A77 1726. In addition, it became evident for the first time that the mechanism involved in this result was the concentration-dependent inhibition of PDK1 phosphorylation, which controls the activation of Akt. These results indicate a new way of controlling mast cells and may therefore be the basis for innovative approaches to the treatment of various diseases related to mast cells.