Talme Toomas, Bergdahl Eva, Sundqvist Karl-Gösta
Department of Medicine, Division of Dermatology, Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.
Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.
Eur J Immunol. 2016 May;46(5):1279-90. doi: 10.1002/eji.201546122. Epub 2016 Apr 13.
Methotrexate (MTX) is a widely used treatment for inflammatory diseases such as rheumatoid arthritis and psoriasis, based on the concept that it is immunosuppressive. Its mechanism of action, however, remains unclear, although it is thought to depend on adenosine. Caffeine and theophylline, which have several targets including adenosine receptors, have been shown to suppress the beneficial clinical effects of MTX. Here we show that MTX and caffeine and theophylline differentially affect a motogenic T-cell mechanism driven by endogenous thrombospondin-1 (TSP-1) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1). MTX stimulated TSP-1 expression and the motogenic TSP-1/TSP-1 receptor mechanism in primary human T cells, hence mimicking IL-2 and CXCL12, which similar to MTX, dampen inflammatory disease. SiRNA-mediated gene silencing of TSP-1 and LRP1 inhibited this stimulatory effect. Caffeine and theophylline inhibited the TSP-1/TSP-1 receptor mechanism by inhibiting LRP1 expression. These results indicate that the effect of MTX on T cells is immunoregulatory rather than immunosuppressive, and suggest a pathway dependent on TSP-1/TSP-1 receptor interactions for the regulation of immune responses.
甲氨蝶呤（MTX）是一种广泛用于治疗类风湿性关节炎和牛皮癣等炎症性疾病的药物，其依据是它具有免疫抑制作用。然而，尽管人们认为其作用机制依赖于腺苷，但其确切作用机制仍不清楚。咖啡因和茶碱有多个作用靶点，包括腺苷受体，已被证明会抑制MTX的临床疗效。在此我们表明，MTX与咖啡因和茶碱对由内源性血小板反应蛋白-1（TSP-1）及其受体低密度脂蛋白受体相关蛋白1（LRP1）驱动的促运动性T细胞机制有不同影响。MTX刺激原代人T细胞中TSP-1的表达以及促运动性TSP-1/TSP-1受体机制，因此类似于IL-2和CXCL12，MTX可减轻炎症性疾病。RNA干扰介导的TSP-1和LRP1基因沉默抑制了这种刺激作用。咖啡因和茶碱通过抑制LRP1的表达来抑制TSP-1/TSP-1受体机制。这些结果表明，MTX对T细胞的作用是免疫调节而非免疫抑制，并提示了一条依赖于TSP-1/TSP-1受体相互作用来调节免疫反应的途径。
