In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1
In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1
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DOI：
10.1182/blood-2008-04-151753
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发表时间：
2008-11-01
期刊：
影响因子：
20.3
通讯作者：
Coller, Barry S.
中科院分区：
文献类型：
--
作者：
Ahamed, Jasimuddin;Burg, Nathalie;Coller, Barry S.
转化生长因子-β 1（TGF-β 1）在亚纳摩尔浓度下对多种细胞类型具有强有力的生理和病理作用。血小板含有的TGF-β 1是其他细胞的40倍，并以与潜伏相关肽（LTP）复合的无活性（潜伏）形式分泌，LTP通过Cys 33与潜伏TGF-β结合蛋白1（LTBP-1）二硫键结合。关于潜伏的TGF-β 1如何在体内被激活知之甚少。在这里，我们表明，从血小板或成纤维细胞释放的TGF-β 1经历了戏剧性的激活时，受到搅拌或剪切力，提供了一个潜在的生理控制机制。基于巯基反应性试剂的作用和搅拌或剪切前后TGF-β 1巯基标记的差异，巯基二硫键交换似乎有助于该过程。活化需要LTBP的存在，因为当作为重组纯化蛋白复合物或在血小板释放物或经工程改造含有LTBP C33 S突变的小鼠血清中进行研究时，仅与LTBP复合的复合物中所含的TGF-β 1不能通过搅拌活化。在血栓形成后5分钟，在小鼠模型中证实了体内潜伏的TGF-β 1的释放和活化。这些数据潜在地为TGF-β 1的体内活化提供了新的机制。（血。2008; 112：3650-3660）
Transforming growth factor-beta 1 (TGF-beta 1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-beta 1 as other cells and secrete it as an inactive ( latent) form in complex with latency-associated peptide ( LAP), which is disulfide bonded via Cys33 to latent TGF-beta binding protein 1 (LTBP-1). Little is known about how latent TGF-beta 1 becomes activated in vivo. Here we show that TGF-beta 1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thioldisulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-beta 1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-beta 1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release and activation of latent TGF-beta 1 in vivo was demonstrated in a mouse model 5 minutes after thrombus formation. These data potentially provide a novel mechanism for in vivo activation of TGF-beta 1. (Blood. 2008; 112: 3650-3660)