Liu Xiangde
Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Cell Motil Cytoskeleton. 2008 Dec;65(12):935-44. doi: 10.1002/cm.20315.
Epithelial-mesenchymal transition (EMT) is believed to play an important role in fibrosis and tumor invasion. EMT can be induced in vitro cell culture by various stimuli including growth factors and matrix metalloproteinases. In this study, we report that cytomix (a mixture of IL-1beta, TNF-alpha and IFN-gamma) significantly enhances TGF-beta1-induced EMT in A549 cells as evidenced by acquisition of fibroblast-like cell shape, loss of E-cadherin, and reorganization of F-actin. IL-1beta or TNF-alpha alone can also augment TGF-beta1-induced EMT. However, a combination of IL-1beta and TNF-alpha or the cytomix is more potent to induce EMT. Cytomix, but not individual cytokine of IL-1beta, TNF-alpha or IFN-gamma, significantly up-regulates expression of TGF-beta receptor type I (TbetaR-I). Suppression of TbetaR-I, Smad2 or Smad3 by siRNA partially blocks EMT induction by cytomix plus TGF-beta1, indicating cytomix augments TGF-beta1-induced EMT through enhancing TbetaR-I and Smad signaling. These results indicate that inflammatory cytokines together with TGF-beta1 may play an important role in the development of fibrosis and tumor progress via the mechanism of epithelial-mesenchymal transition.
上皮-间质转化（EMT）被认为在纤维化和肿瘤侵袭中起重要作用。EMT可在体外细胞培养中由包括生长因子和基质金属蛋白酶在内的多种刺激诱导产生。在本研究中，我们报告细胞混合因子（IL-1β、TNF-α和IFN-γ的混合物）显著增强TGF-β1诱导的A549细胞上皮-间质转化，表现为获得成纤维细胞样细胞形态、E-钙黏蛋白丢失以及F-肌动蛋白重组。单独的IL-1β或TNF-α也可增强TGF-β1诱导的上皮-间质转化。然而，IL-1β和TNF-α的组合或细胞混合因子诱导上皮-间质转化的作用更强。细胞混合因子而非IL-1β、TNF-α或IFN-γ单个细胞因子可显著上调I型TGF-β受体（TβR-I）的表达。通过小干扰RNA抑制TβR-I、Smad2或Smad3可部分阻断细胞混合因子加TGF-β1诱导的上皮-间质转化，表明细胞混合因子通过增强TβR-I和Smad信号增强TGF-β1诱导的上皮-间质转化。这些结果表明，炎性细胞因子与TGF-β1一起可能通过上皮-间质转化机制在纤维化发展和肿瘤进展中起重要作用。
