LAP degradation product reflects plasma kallikrein-dependent TGF-β activation in patients with hepatic fibrosis.
LAP degradation product reflects plasma kallikrein-dependent TGF-β activation in patients with hepatic fibrosis.
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DOI：
10.1186/2193-1801-3-221
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Kojima S
中科院分区：
文献类型：
--
作者：
Hara M;Kirita A;Kondo W;Matsuura T;Nagatsuma K;Dohmae N;Ogawa S;Imajoh-Ohmi S;Friedman SL;Rifkin DB;Kojima S
细胞因子激活的副产物有时可用作监测患者细胞因子生成的替代生物标志物。转化生长因子（TGF）-β在肝纤维化的发病机制中发挥着关键作用。 TGF-β 作为非活性潜伏复合物的一部分产生，其中细胞因子被其前肽、潜伏相关蛋白 (LAP) 捕获。因此，为了发挥其生物活性，TGF-β必须从潜在复合物中释放出来。几种蛋白酶通过切割 LAP 来激活潜在的 TGF-β。我们之前报道过卡莫司他甲磺酸盐是一种广谱蛋白酶抑制剂，特别有效地抑制血浆激肽释放酶（PLK），可预防猪血清诱导的大鼠肝纤维化模型中的肝纤维化。我们认为，在动物模型的肝病发病机制中，PLK 可能作为潜在 TGF-β 的激活剂。然而，这种激活机制是否也在患者纤维化肝脏中发挥作用仍有待阐明。在这里，我们报告 PLK 在 R58 和 L59 残基之间切割 LAP。我们通过 PLK 生产了针对两种 LAP 降解产物 (LAP-DP) 的单克隆抗体，并使用这些特异性抗体对纤维化动物和患者肝组织中的 LAP-DP 进行免疫染色。在肝组织中检测到终止于R58的N端侧LAP-DP（R58 LAP-DP），而起始于L59的C端侧LAP-DP（L59 LAP-DP）未检测到。 R58 LAP-DP 主要见于 α-平滑肌肌动蛋白阳性激活的星状细胞。这些数据首次表明患者体内发生了 PLK 依赖性 TGF-β 激活反应，并表明 LAP-DP 可用作反映动物模型和患者纤维化肝中 PLK 依赖性 TGF-β 激活的替代标记。本文的在线版本 (doi:10.1186/2193-1801-3-221) 包含补充材料，可供授权用户使用。
Byproducts of cytokine activation are sometimes useful as surrogate biomarkers for monitoring cytokine generation in patients. Transforming growth factor (TGF)-β plays a pivotal role in pathogenesis of hepatic fibrosis. TGF-β is produced as part of an inactive latent complex, in which the cytokine is trapped by its propeptide, the latency-associated protein (LAP). Therefore, to exert its biological activity, TGF-β must be released from the latent complex. Several proteases activate latent TGF-β by cutting LAP. We previously reported that Camostat Mesilate, a broad spectrum protease inhibitor, which is especially potent at inhibiting plasma kallikrein (PLK), prevented liver fibrosis in the porcine serum-induced liver fibrosis model in rats. We suggested that PLK may work as an activator of latent TGF-β during the pathogenesis of liver diseases in the animal models. However, it remained to be elucidated whether this activation mechanism also functions in fibrotic liver in patients. Here, we report that PLK cleaves LAP between R58 and L59 residues. We have produced monoclonal antibodies against two degradation products of LAP (LAP-DP) by PLK, and we have used these specific antibodies to immunostain LAP-DP in liver tissues from both fibrotic animals and patients. The N-terminal side LAP-DP ending at R58 (R58 LAP-DP) was detected in liver tissues, while the C-terminal side LAP-DP beginning at L59 (L59 LAP-DP) was not detectable. The R58 LAP-DP was seen mostly in α-smooth muscle actin-positive activated stellate cells. These data suggest for the first time that the occurrence of a PLK-dependent TGF-β activation reaction in patients and indicates that the LAP-DP may be useful as a surrogate marker reflecting PLK-dependent TGF-β activation in fibrotic liver both in animal models and in patients. The online version of this article (doi:10.1186/2193-1801-3-221) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/j.bbadis.2012.10.005
发表时间：
2013-07
影响因子：
6.2
作者：
Henderson, Neil C.;Sheppard, Dean
通讯作者：
Sheppard, Dean
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影响因子：
7.8
作者：
Lyons, R M;Gentry, L E;Purchio, A F;Moses, H L
通讯作者：
Moses, H L
影响因子：
82.9
作者：
通讯作者：
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影响因子：
13.5
作者：
Bedossa, P;Poynard, T
通讯作者：
Poynard, T
DOI：
10.1083/jcb.106.5.1659
发表时间：
1988-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lyons RM;Keski-Oja J;Moses HL
通讯作者：
Moses HL