Fibronectin Peptides as Potential Regulators of Hepatic Fibrosis Through Apoptosis of Hepatic Stellate Cells
Fibronectin Peptides as Potential Regulators of Hepatic Fibrosis Through Apoptosis of Hepatic Stellate Cells
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DOI：
10.1002/jcp.24714
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发表时间：
2015-03-01
影响因子：
5.6
通讯作者：
Lopez-Zabalza, Maria J.
中科院分区：
文献类型：
--
作者：
Modol, Teresa;Brice, Natalia;Lopez-Zabalza, Maria J.
细胞外基质（extracellular matrix， ECM）成分的转换可以产生调节多种细胞功能的信号，如增殖、分化和凋亡。在肝损伤期间，基质金属蛋白酶（MMPs）的产生增强，细胞外基质蛋白衍生的肽水平增加。在细胞外基质蛋白中存在序列的合成肽先前被发现对包括炎症细胞单核/巨噬细胞在内的几种细胞类型诱导刺激和凋亡作用。因此，在炎症性肝病中，局部积累的肽也可能通过诱导肝星状细胞（HSC）的凋亡来调节肝纤维化，HSC是细胞外基质成分的主要细胞来源。本研究基于寡核体DNA断裂、caspase-3和-9激活、Bcl-2缺失和Bax蛋白积累，描述了纤连蛋白肽对人肝星状细胞LX-2的凋亡作用。我们还发现这些肽触发Src激酶的激活，进而介导JNK和p38活性的增加。通过使用特异性抑制剂，我们证实Src、JNK和p38参与了纤连蛋白肽在HSC上诱导的细胞凋亡。此外，纤连蛋白肽增加了人HSC中iNOS的表达，特异性抑制iNOS可显著降低JNK的持续活性和这些肽引起的程序性细胞死亡。最后，纤维连接蛋白肽在肝纤维化中的可能调节作用进一步得到了这些肽在人单核细胞中诱导金属蛋白酶-9 （MMP-9）表达能力的支持。j .细胞。中国生物医学工程学报，2016,31(2):546-553。(c) 2014 Wiley Periodicals, Inc., A Wiley Company
The turnover of extracellular matrix (ECM) components can generate signals that regulate several cellular functions such as proliferation, differentiation, and apoptosis. During liver injury, matrix metalloproteases (MMPs) production is enhanced and increased levels of peptides derived from extracellular matrix proteins can be generated. Synthetic peptides with sequences present in extracellular matrix proteins were previously found to induce both stimulating and apoptotic effects on several cell types including the inflammatory cells monocytes/macrophages. Therefore, in inflammatory liver diseases, locally accumulated peptides could be also important in regulating hepatic fibrosis by inducing apoptosis of hepatic stellate cells (HSC), the primary cellular source of extracellular matrix components. Here, we describe the apoptotic effect of fibronectin peptides on the cell line of human hepatic stellate cells LX-2 based on oligonucleosomal DNA fragmentation, caspase-3 and -9 activation, Bcl-2 depletion, and accumulation of Bax protein. We also found that these peptides trigger the activation of Src kinase, which in turn mediated the increase of JNK and p38 activities. By the use of specific inhibitors we demonstrated the involvement of Src, JNK, and p38 in apoptosis induced by fibronectin peptides on HSC. Moreover, fibronectin peptides increased iNOS expression in human HSC, and specific inhibition of iNOS significantly reduced the sustained activity of JNK and the programmed cell death caused by these peptides. Finally, the possible regulatory effect of fibronectin peptides in liver fibrosis was further supported by the ability of these peptides to induce metalloprotease-9 (MMP-9) expression in human monocytes. J. Cell. Physiol. 230: 546-553, 2015. (c) 2014 Wiley Periodicals, Inc., A Wiley Company