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首页> 外文期刊>Cellular Signalling >Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells
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Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells

机译：大鼠胰腺星状细胞中结缔组织生长因子作用的分子见解

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摘要

Pancreatic fibrosis, a key feature of chronic pancreatitis and pancreatic cancer. is mediated by activated pancreatic stellate cells (PSC). Connective tissue growth factor (CTGF) has been suggested to play a major role in fibrogenesis by enhancing PSC activation after binding to alpha 5 beta 1 integrin. Here, we have focussed on molecular determinants of CTGF action. Inhibition of CTGF expression in PSC by siRNA was associated with decreased proliferation, while application of exogenous CTGF stimulated both cell growth and collagen synthesis. Real-time PCR studies revealed that CTGF target genes in PSC not only include mediators of matrix remodelling but also the proinflammatory cytokines interleukin (IL)-1 beta and IL-6. CTGF stimulated binding of NF-kappa B to the IL-6 promoter, and siRNA targeting the NF-kappa B subunit RelA interfered with CTGF-incluced IL-6 expression, implicating the NF-kappa B pathway in the mediation of the CTGF effect. In further studies, we have analyzed regulation of CTGF expression in PSC. Transforming growth factor-beta 1, activin A and tumor necrosis factor-alpha enhanced expression of the CTGF gene, while interferon-gamma displayed the opposite effect. The region from -74 to -125 of the CTGF promoter was revealed to be critical for its activity in PSC as well as for the inhibitory effect of interferon-gamma. Taken together, our results indicate a tight control of CTGF expression in PSC at the transcriptional level. CTGF promotes fibrogenesis both directly by enhancing PSC proliferation and matrix protein synthesis, and indirectly through the release of proinflammatory cytokines that may accelerate the process of chronic inflammation. (C) 2008 Elsevier Inc. All rights reserved.
机译：胰腺纤维化，慢性胰腺炎和胰腺癌的关键特征。由活化的胰星形细胞（PSC）介导。已经提出了结缔组织生长因子（CTGF）在结合α5β1整联蛋白后通过增强PSC活化来发挥纤维发生中的主要作用。在这里，我们侧重于CTGF作用的分子决定因素。 SiRNA抑制CTGF在PSC中的表达与增殖降低相关，而外源CTGF的应用刺激了细胞生长和胶原合成。实时PCR研究表明，PSC中的CTGF靶基因不仅包括基质重塑的介质，还包括促炎细胞因子白细胞介素（IL）-1β和IL-6。 CTGF刺激NF-Kappa B的结合到IL-6启动子，靶向NF-Kappa B亚基rela干扰CTGF延伸的IL-6表达的siRNA，暗指CTGF效应的中介中的NF-Kappa B途径。在进一步的研究中，我们在PSC中分析了CTGF表达的调节。转化生长因子-β1，激活素A和肿瘤坏死因子-α增强CTGF基因的表达，而干扰素-γ显示出相反的效果。 CTGF启动子的-74至-125的区域被揭示为其在PSC中的活性至关重要，以及干扰素-γ的抑制作用。连同，我们的结果表明在转录水平下PSC中CTGF表达的紧密控制。 CTGF通过提高PSC增殖和基质蛋白质合成直接促进纤维发生，并且间接通过释放可能加速慢性炎症过程的促炎细胞因子。 （c）2008年elestvier Inc.保留所有权利。

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