Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation
Diverse signaling pathways regulate fibroblast differentiation and transformation through Rho kinase activation
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DOI：
10.1002/jcp.20939
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发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Siddiqui, Rafat A.
中科院分区：
文献类型：
--
作者：
Harvey, Kevin A.;Paranavitana, Corine Nivanka;Siddiqui, Rafat A.
本研究探讨了激动剂诱导的Rho激酶（ROCK）参与肺源性成纤维细胞形态学结果的作用。正常人肺成纤维细胞（NHLF）在二维生长因子减少的基于Matrigel基质的测定中自发分化成网络样结构。鞘氨醇1-磷酸（SPP），一种调节血管生成的生物活性磷脂，以剂量依赖性方式抑制成纤维细胞形态发生，在500 nM时几乎消除了多细胞结构的存在。用Rho激酶特异性抑制剂H1152预处理可消除高剂量SPP诱导的抑制作用。类似地，用Rho激酶siRNA转染的NHLF阻止SPP诱导的成纤维细胞形态发生的抑制。或者，转化生长因子-β 1（TGF-β 1），一种被认为是伤口愈合的关键介质的细胞因子，终末将NHLF分化为肌成纤维细胞，如α-肌动蛋白（α-SMA）的平滑肌细胞同种型的表达所证明的。H1152以剂量依赖性方式抑制TGF-β 1诱导的α-SMA表达。类似地，用Rho激酶siRNA处理使α-SMA表达降低超过50%。SPP处理对TGF-β 1诱导的向肌成纤维细胞的转化没有影响，并且TGF-β 1处理不改变成纤维细胞的形态发生。这项研究表明，Rho激酶在成纤维细胞的细胞调节中具有双重调节作用，其中SPP通过G蛋白偶联受体诱导的Rho激酶活化抑制成纤维细胞形态发生，而TGF-β 1通过丝氨酸/苏氨酸激酶受体诱导的Rho激酶活化最终转化为肌成纤维细胞。
This study examined the role of agonist-induced Rho kinase (ROCK) involvement in the morphological outcome of pulmonary-derived fibroblasts. Normal human lung fibroblasts (NHLF) spontaneously differentiate into network-like structures in a two-dimensional growth factor reduced Matrigel matrix-based assay. Sphingosine 1-phosphate (SPP), a bioactive phospholipid that regulates angiogenesis, inhibited fibroblast morphogenesis in a dose-dependent manner, virtually eliminating the presence of multi-cellular structures at 500 nM. Pretreatment with the Rho kinase-specific inhibitor, H1152, eradicated the high dose SPP-induced inhibition. Similarly, NHLFs transfected with Rho kinase siRNA prevented SPP-induced inhibition of the fibroblast morphogenesis. Alternatively, transforming growth factor-beta 1 (TGF-beta 1), a cytokine recognized as a key mediator of wound healing, terminally differentiates NHLF into myofibroblasts as evidenced by the expression of the smooth muscle cell isoform of alpha-actin (alpha-SMA). H1152 suppressed TGF-beta 1-induced alpha-SMA expression in a dose-dependent manner. Similarly, treatment with Rho kinase siRNA reduced alpha-SMA expression by greater than 50%. SPP treatment had no effect on TGF-beta 1-induced transformation into myofibroblasts, and TGF-beta 1 treatment did not alter fibroblast morphogenesis. This study suggests a dual regulatory role for Rho kinase in cellular regulation of fibroblasts in which SPP-induced Rho kinase activation via a G-protein coupled receptor suppresses fibroblast morphogenesis while TGF-beta 1-induced Rho kinase activation through a serine/threonine kinase receptor culminates in transformation into myofibroblasts.