The Immunosuppressor Mycophenolic Acid Kills Activated Lymphocytes by Inducing a Nonclassical Actin-Dependent Necrotic Signal
The Immunosuppressor Mycophenolic Acid Kills Activated Lymphocytes by Inducing a Nonclassical Actin-Dependent Necrotic Signal
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DOI：
10.4049/jimmunol.181.11.7630
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发表时间：
2008-12-01
影响因子：
4.4
通讯作者：
Legembre, Patrick
中科院分区：
文献类型：
--
作者：
Chaigne-Delalande, Benjamin;Guidicelli, Gwendaline;Legembre, Patrick
霉酚酸酯（MMF）是一种用于移植的免疫抑制剂。在过去的十年中，霉酚酸酯也已成为一种替代治疗方案的自身免疫性疾病，主要是对患者难治性的其他疗法。霉酚酸（MPA）是霉酚酸的活性化合物，通过阻断肌苷一磷酸脱氢酶消耗细胞内的三磷酸鸟苷池。在抑制肌苷一磷酸脱氢酶后，T和B淋巴细胞的消除所涉及的分子机制仍然难以捉摸。在这项研究中，我们发现，在对比的免疫抑制剂硫唑嘌呤，环孢素A，和他克莫司，MPA杀死淋巴细胞通过激活半胱天冬酶非依赖性坏死信号。此外，MPA介导的坏死信号依赖于一种新的细胞内信号的传输，涉及Rho-GTdR Cdc 42活性和肌动蛋白聚合。除了它的医学利益，这项研究揭示了一个新的和非典型的分子机制，导致坏死细胞死亡。免疫学杂志，2008，181：7630-7638.
Mycophenolate mofetil (MMF) is an immunosuppressive agent used in transplantation. Over the last decade, MMF has also emerged as an alternative therapeutic regimen for autoimmune diseases, mainly for patients refractory to other therapies. The active compound of MMF, mycophenolic acid (MPA), depletes the intracellular pool of guanosine tri-phosphate through inosine monophosphate dehydrogenase blockade. The molecular mechanism involved in the elimination of T and B lymphocytes upon inhibition of inosine monophosphate dehydrogenase remains elusive. In this study, we showed that in contrast to the immuno-suppressors azathioprine, cyclosporin A, and tacrolimus, MPA killed lymphocytes through the activation of a caspase-independent necrotic signal. Furthermore, the MPA-mediated necrotic signal relied on the transmission of a novel intracellular signal involving Rho-GTPase Cdc42 activity and actin polymerization. In addition to its medical interest, this study sheds light on a novel and atypical molecular mechanism leading to necrotic cell death. The Journal of Immunology, 2008, 181: 7630-7638.