Profibrotic TGFβ responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases
Profibrotic TGFβ responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases
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DOI：
10.1096/fj.12-224907
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发表时间：
2013-11-01
期刊：
影响因子：
4.8
通讯作者：
Leof, Edward B.
中科院分区：
文献类型：
--
作者：
Andrianifahanana, Mahefatiana;Wilkes, Mark C.;Leof, Edward B.
转化生长因子在体内外均具有显著的促纤维化作用。这反映了其刺激纤维化介质和诱导其他促纤维化细胞因子的表达的能力，如血小板衍生生长因子(PDGF)和表皮生长因子(EGF/ErbB)配体。在这里，我们讨论了转化生长因子诱导ErbB配体的机制以及抑制多种转化生长因子调节过程的生理学意义。文献证明ErbB配体的诱导需要PDGF受体(PDGFR)的介导，并通过ErbB受体参与正的自分泌/旁分泌反馈环。虽然PDGFRs是转化生长因子刺激的ErbB配体上调所必需的，但转化生长因子特异的信号也是激活ErbB受体所必需的。随后的促纤维化反应被证明涉及PDGF和ErbB信号的协同作用。此外，使用博莱霉素诱导的肺纤维化的小鼠治疗模型，我们发现伊马替尼和拉帕替尼分别抑制转化生长因子/PDGF和ErbB通路，不仅比单独使用这两种药物更大程度地阻止了肌成纤维细胞基因的表达，而且基本上稳定了作为肺功能总体指标的气体交换(氧饱和度)。这些观察为纤维化前的转化生长因子信号转导提供了重要的机制洞察，并表明靶向多种细胞因子是一种可能的策略来改善依赖于TGF的器官纤维化。Andrianifahanana，M.，Wilkes，M.C.，Gupta，S.K.，Rahimi，R.R.，Repellin，C.E.，Edens，M.，Wittenberger，J.，Yen，X.，Maidl，E.，Becker，J.，Leof，E.B.纤维化转化生长因子的反应需要PDGF和ErbB受体酪氨酸激酶的协同作用。
Transforming growth factor (TGF) has significant profibrotic activity both in vitro and in vivo. This reflects its capacity to stimulate fibrogenic mediators and induce the expression of other profibrotic cytokines such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF/ErbB) ligands. Here we address both the mechanisms by which TGF induced ErbB ligands and the physiological significance of inhibiting multiple TGF-regulated processes. The data document that ErbB ligand induction requires PDGF receptor (PDGFR) mediation and engages a positive autocrine/paracrine feedback loop via ErbB receptors. Whereas PDGFRs are essential for TGF-stimulated ErbB ligand up-regulation, TGF-specific signals are also required for ErbB receptor activation. Subsequent profibrotic responses are shown to involve the cooperative action of PDGF and ErbB signaling. Moreover, using a murine treatment model of bleomycin-induced pulmonary fibrosis we found that inhibition of TGF/PDGF and ErbB pathways with imatinib plus lapatinib, respectively, not only prevented myofibroblast gene expression to a greater extent than either drug alone, but also essentially stabilized gas exchange (oxygen saturation) as an overall measure of lung function. These observations provide important mechanistic insights into profibrotic TGF signaling and indicate that targeting multiple cytokines represents a possible strategy to ameliorate organ fibrosis dependent on TGF.Andrianifahanana, M., Wilkes, M. C., Gupta, S. K., Rahimi, R. R., Repellin, C. E., Edens, M., Wittenberger, J., Yin, X., Maidl, E., Becker, J., Leof, E. B. Profibrotic TGF responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases.