The recombinant proregion of transforming growth factor beta 1 (Latency-associated peptide) inhibits active transforming growth factor beta 1 in transgenic mice
The recombinant proregion of transforming growth factor beta 1 (Latency-associated peptide) inhibits active transforming growth factor beta 1 in transgenic mice
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DOI：
10.1073/pnas.93.12.5877
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发表时间：
1996-06-11
影响因子：
11.1
通讯作者：
Sporn, MB
中科院分区：
文献类型：
--
作者：
Bottinger, EP;Factor, VM;Sporn, MB
转化生长因子 β 的所有三种亚型（TGF-β 1、TGF-β 2 和 TGF-β 3）均作为潜在复合物分泌并在细胞外激活，导致成熟细胞因子从其非共价相关前区（也称为潜伏相关肽 (LAP)）中释放。TGF-β 1 的 LAP 区域在 杆状病毒表达系统并纯化至同质。 TGF-β 介导的生长抑制和基因诱导的体外测定表明，重组 TGF-β 1 LAP 是 TGF-β 1、-β 2 和 -β 3 活性的有效抑制剂。50% 中和 TGF-β 活性的 LAP 有效剂量范围为 4.7 至 80 倍摩尔过量，具体取决于 TGF-β 同工型 和活动检查。使用 (125) 标记的 LAP，我们表明腹膜内施用途径对于 LAP 的全身给药是有效的，组织中 LAP 浓度的比较显示，除心脏和肌肉外，大多数器官中 LAP 的水平均低 4 至 1 倍，在生物活性 TGF-β 1 肝脏水平升高的转基因小鼠中，用重组 LAP 完全治疗 逆转部分肝切除术后残余肝脏中 TGF-β1 诱导的早期增殖反应的抑制。结果表明，重组LAP在体外和体内都是生物活性TGF-β的有效抑制剂，腹膜内给药后，重组LAP应该成为研究和治疗性调节TGF-β介导的病理生理过程的新方法的有用工具。
All three isoforms of transforming growth factors beta (TGF-beta 1, TGF-beta 2, and TGF-beta 3) are secreted as latent complexes and activated extracellularly, leading to the release of the mature cytokines from their noncovalently associated proregions, also known as latency-associated peptides (LAPs), The LAP region of TGF-beta 1 was expressed in a baculovirus expression system and purified to homogeneity. In vitro assays of growth inhibition and gene induction mediated by TGF-beta demonstrate that recombinant TGF-beta 1 LAP is a potent inhibitor of the activities of TGF-beta 1, -beta 2, and -beta 3, Effective dosages of LAP for 50% neutralization of TGF-beta activities range from 4.7- to 80-fold molar excess depending on the TGF-beta isoform and activity examined. Using (125)-labeled LAP, we show that the intraperitoneal application route is effective for systemic administration of LAP, Comparison of concentrations of LAP in tissues shows a homogenous pattern in most organs with the exception of heart and muscle, in which levels of LAP are 4- to I-fold lower, In transgenic mice with elevated hepatic levels of bioactive TGF-beta 1, treatment with recombinant LAP completely reverses suppression of the early proliferative response induced by TGF-beta 1 in remnant livers after partial hepatectomy. The results suggest that recombinant LAP is a potent inhibitor of bioactive TGF-beta both in vitro and in vivo, after intraperitoneal administration, Recombinant LAP should be a useful tool for novel approaches to study and therapeutically modulate pathophysiological processes mediated by TGF-beta.