Tiede Imke, Fritz Gerhard, Strand Susanne, Poppe Daniela, Dvorsky Radovan, Strand Dennis, Lehr Hans Anton, Wirtz Stefan, Becker Christoph, Atreya Raja, Mudter Jonas, Hildner Kai, Bartsch Brigitte, Holtmann Martin, Blumberg Richard, Walczak Henning, Iven Heiko, Galle Peter R, Ahmadian Mohammad Reza, Neurath Markus F
Laboratory of Immunology, Department of Medicine, University of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany.
J Clin Invest. 2003 Apr;111(8):1133-45. doi: 10.1172/JCI16432.
Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L) was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation.
硫唑嘌呤及其代谢产物6-巯基嘌呤（6-MP）是免疫抑制药物，用于器官移植以及自身免疫性疾病和慢性炎症性疾病，如克罗恩病。然而，它们的分子作用机制尚不清楚。在本研究中，我们发现硫唑嘌呤及其代谢产物在通过调节CD28共刺激时的Rac1激活来控制T细胞凋亡方面具有独特且意想不到的作用。我们发现硫唑嘌呤及其代谢产物可诱导克罗恩病患者和对照患者的T细胞凋亡。诱导凋亡需要CD28共刺激，并且是通过硫唑嘌呤生成的6-硫代鸟嘌呤三磷酸（6-Thio-GTP）与Rac1而非GTP结合，特异性阻断Rac1激活来介导的。硫唑嘌呤抑制Rac1靶基因如丝裂原活化蛋白激酶激酶（MEK）、核因子κB和bcl-x(L)的激活，导致凋亡的线粒体途径。因此，硫唑嘌呤通过调节Rac1活性将共刺激信号转化为凋亡信号。这些发现解释了硫唑嘌呤的免疫抑制作用，并表明6-Thio-GTP衍生物可能作为自身免疫性疾病和器官移植中有效的免疫抑制剂。
