Hyper-responsiveness of IPF/UIP fibroblasts:: Interplay between TGFβ1, IL-13 and CCL2
Hyper-responsiveness of IPF/UIP fibroblasts:: Interplay between TGFβ1, IL-13 and CCL2
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DOI：
10.1016/j.biocel.2008.02.016
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发表时间：
2008-01-01
影响因子：
4
通讯作者：
Das, Anuk M.
中科院分区：
文献类型：
--
作者：
Murray, Lynne A.;Argentieri, Rochelle L.;Das, Anuk M.
具有常见间质性肺炎组织学病理学（IPF/UIP）的特发性肺纤维化的标志之一是由于增强的成纤维细胞外基质合成活性导致的过量胶原沉积。使用肺纤维化的鼠模型的研究已经阐明了涉及IL-13驱动CCL 2的促纤维化途径，CCL 2又驱动肺成纤维细胞中的TGF β 1。因此，我们试图通过评价人IPF/UIP成纤维细胞来确定该途径是否存在于人纤维化环境中。与非纤维化成纤维细胞相比，IPF/UIP成纤维细胞具有增加的基线纤维化表型。有趣的是，非纤维化成纤维细胞以促纤维化方式对TGF β 1应答，但对IL-13或CCL 2相对不应答，而IPF/UIP细胞对TGF β 1、IL-13和CCL 2高度应答。有趣的是，TGF β 1、CCL 2和IL-13均上调TGF β受体和IL-13受体的表达，表明介体能够调节彼此的功能。此外，在体内，在博来霉素诱导的肺纤维化过程中，JE和MCP 5（CCL 2的两个功能性直系同源物）的中和显著减少胶原沉积以及JE和CCR 2表达。同样在博来霉素模型中，在TGF β刺激后高度诱导的CrGF用抗JE/抗MCP 5处理减弱。总的来说，这项研究证明了TGF β 1，IL-13和CCL 2在IPF/UIP中的相互作用，其中这三种介质相互反馈，促进纤维化反应。(C)2008爱思唯尔有限公司保留所有权利。
One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology (IPF/UIP) is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving IL-13 driving CCL2, which in turn drives TGF beta 1 in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human IPF/UIP fibroblasts. IPF/UIP fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to TGF beta 1 but were relatively non-responsive to IL-13 or CCL2, whereas, IPF/UIP cells were hyper-responsive to TGF beta 1, IL-13 and CCL2. Interestingly, TGF beta 1, CCL2 and IL-13 all upregulated TGF beta receptor and IL-13 receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of CCL2, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CrGF, which is highly induced following TGF beta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between TGF beta 1, IL-13 and CCL2 in IPF/UIP, where these three mediators feedback on each other, promoting the fibrotic response. (C) 2008 Elsevier Ltd. All rights reserved.