Hara Mitsuko, Matsuura Tomokazu, Kojima Soichi
Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, 2-1 Hirosawa, Wako, Saitama, 351-0918, Japan
Department of Laboratory Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan
While there are many blood and/or tissue biomarkers as well as algorithms clinically used to assess hepatic fibrosis, a good biomarker and therapeutic target of hepatic fibrogenesis, which reflects prefibrotic changes, has not been established. The most fibrogenic cytokine, transforming growth factor (TGF)-β, is produced as a latent complex, in which TGF-β is trapped by its propeptide. On the surface of activated hepatic stellate cells, plasma kallikrein activates TGF-β by cleaving latency-associated protein (LAP) between the R and L residues, releasing active TGF-β from the complex. We made specific antibodies that recognize neo-C-terminal (R) and N-terminal (L) ends of LAP degradation products (LAP-DPs) and found that LAP-DPs may serve as a novel surrogate marker of TGF-β activation—namely, generation of active TGF-β—and is thus a therapeutic marker for TGF-β-mediated liver fibrogenesis in patients and can also be used to monitor effects of anti-fibrogenic factors or compounds for discovery of a novel anti-fibrosis drug.
虽然临床上有许多血液和/或组织生物标志物以及算法用于评估肝纤维化，但尚未建立一个能反映纤维化前变化的良好的肝纤维化生物标志物和治疗靶点。最具纤维化作用的细胞因子——转化生长因子（TGF）-β，是以潜伏复合物的形式产生的，其中TGF-β被其前肽所捕获。在活化的肝星状细胞表面，血浆激肽释放酶通过切割潜伏相关蛋白（LAP）的R和L残基之间的肽段来激活TGF-β，从复合物中释放出活性TGF-β。我们制备了特异性抗体，可识别LAP降解产物（LAP-DPs）的新C末端（R）和N末端（L），并发现LAP-DPs可能作为TGF-β激活的一种新型替代标志物——即活性TGF-β的产生——因此是患者中TGF-β介导的肝纤维化的治疗标志物，也可用于监测抗纤维化因子或化合物的效果，以发现新型抗纤维化药物。
