Inflammatory cytokines augments TGF-β1-induced epithelial-mesenchymal transition in A549 cells by up-regulating TβR-I

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-1β, TNF-α and IFN-γ) significantly enhances TGF-β1-induced EMT in A549 cells as evidenced by acquisition of fibroblast-like cell shape, loss of E-cadherin, and reorganization of F-actin. IL-1β or TNF-α alone can also augment TGF-β1-induced EMT. However, a combination of IL-1β and TNF-α or the cytomix is more potent to induce EMT. Cytomix, but not individual cytokine of IL-1β, TNF-α or IFN-γ, significantly up-regulates expression of TGF-β receptor type I (TβR-I). Suppression of TβR-I, Smad2 or Smad3 by siRNA partially blocks EMT induction by cytomix plus TGF-β1, indicating cytomix augments TGF-β1-induced EMT through enhancing TβR-I and Smad signaling. These results indicate that inflammatory cytokines together with TGF-β1 may play an important role in the development of fibrosis and tumor progress via the mechanism of epithelial-mesenchymal transition.