Inflammatory cytokines augments TGF-beta1-induced epithelial-mesenchymal transition in A549 cells by up-regulating TbetaR-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-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.
Liu
Xiangde
X
Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA. xdliu@unmc.edu
D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology* / Q000502:physiology; D005355:Fibrosis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology* / Q000502:physiology; D009369:Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I