Keller Christina D, Rivera Gil Pilar, Tölle Markus, van der Giet Markus, Chun Jerold, Radeke Heinfried H, Schäfer-Korting Monika, Kleuser Burkhard
Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany.
Am J Pathol. 2007 Jan;170(1):281-92. doi: 10.2353/ajpath.2007.060485.
The novel immunomodulator FTY720 is an effective immunosuppressive agent in experimental models of transplantation and autoimmunity and is currently undergoing phase III clinical trials for multiple sclerosis. Phosphorylated FTY720 is a structural analogue of sphingosine 1-phosphate (S1P) and therefore acts as a high-affinity agonist at four of the five G protein-coupled S1P receptors. It has been well established that there exists a crosstalk between S1P and transforming growth factor (TGF)-beta signaling. Because TGF-beta is the most prominent inductor of fibrosis and myofibroblasts are primarily responsible for excessive matrix protein formation, we examined whether FTY720, in analogy to TGF-beta, induces differentiation of fibroblasts into myofibroblasts. Indeed, FTY720 provoked myofibroblast differentiation comparable with that of TGF-beta. For biological efficacy, FTY720 required endogenous phosphorylation because inhibition of sphingosine kinase completely prevented FTY720 from inducing the differentiation process. Moreover, we identified the lysophospholipid receptor S1P3 as the crucial receptor subtype for FTY720-induced myofibroblast differentiation because the effect was abolished in fibroblasts isolated from S1P3 knockout mice. Finally, we determined that downstream of S1P3 signaling Smad3 activation is essential for myofibroblast differentiation in response to FTY720. Thus, FTY720 may have adverse fibrotic effects related to its activity on S1P3 signaling.
新型免疫调节剂FTY720在移植和自身免疫的实验模型中是一种有效的免疫抑制剂，目前正在进行针对多发性硬化症的III期临床试验。磷酸化的FTY720是1-磷酸鞘氨醇（S1P）的结构类似物，因此在五个G蛋白偶联的S1P受体中的四个上作为高亲和力激动剂起作用。S1P与转化生长因子（TGF）-β信号传导之间存在相互作用，这一点已经得到充分证实。由于TGF-β是纤维化最主要的诱导因子，而成肌纤维细胞主要负责过多的基质蛋白形成，我们研究了FTY720是否与TGF-β类似，诱导成纤维细胞分化为成肌纤维细胞。事实上，FTY720引发的成肌纤维细胞分化与TGF-β相当。为了产生生物学效应，FTY720需要内源性磷酸化，因为抑制鞘氨醇激酶完全阻止了FTY720诱导分化过程。此外，我们确定溶血磷脂受体S1P3是FTY720诱导成肌纤维细胞分化的关键受体亚型，因为从S1P3基因敲除小鼠分离的成纤维细胞中该效应消失。最后，我们确定在S1P3信号传导下游，Smad3激活对于响应FTY720的成肌纤维细胞分化至关重要。因此，FTY720可能因其对S1P3信号传导的活性而具有不良的纤维化作用。
