The Epstein-Barr virus latent membrane protein 1 and transforming growth factor--β1 synergistically induce epithelial--mesenchymal transition in lung epithelial cells

Am J Respir Cell Mol Biol. 2011 Jun;44(6):852-62. doi: 10.1165/rcmb.2009-0232OC. Epub 2010 Aug 6.


The histopathology of idiopathic pulmonary fibrosis (IPF) includes the presence of myofibroblasts within so-called fibroblastic foci, and studies suggest that lung myofibroblasts may be derived from epithelial cells through epithelial--mesenchymal transition (EMT). Transforming growth factor (TGF)-β1 is expressed and/or activated in fibrogenesis, and induces EMT in lung epithelial cells in a dose-dependent manner. A higher occurrence of Epstein-Barr virus (EBV) has been reported in the lung tissue of patients with IPF. EBV expresses latent membrane protein (LMP) 1 during the latent phase of infection, and may play a role in the pathogenesis of pulmonary fibrosis inasmuch as LMP-1 may act as a constitutively active TNF-α receptor. Our data show a remarkable increase in mesenchymal cell markers, along with a concurrent reduction in the expression of epithelial cell markers in lung epithelial cells cotreated with LMP-1, and very low doses of TGF-β1. This effect was mirrored in lung epithelial cells infected with EBV expressing LMP1 and cotreated with TGF-β1. LMP1 pro-EMT signaling was identified, and occurs primarily through the nuclear factor-κB pathway and secondarily through the extracellular signal--regulated kinase (ERK) pathway. Activation of the ERK pathway was shown to be critical for aspects of TGF-β1-induced EMT. LMP1 accentuates the TGF-β1 activation of ERK. Together, these data demonstrate that the presence of EBV-LMP1 in lung epithelial cells synergizes with TGF-β1 to induce EMT. Our in vitro data may help to explain the observation that patients with IPF demonstrating positive staining for LMP1 in lung epithelial cells have a more rapid demise than patients in whom LMP1 is not detected.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Epithelial Cells / cytology*
  • Epithelial-Mesenchymal Transition
  • Fibrosis / pathology
  • Herpesvirus 4, Human / metabolism
  • Humans
  • Lung / cytology*
  • Lung / pathology
  • Mesoderm / cytology
  • Models, Biological
  • NF-kappa B / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta1 / metabolism*
  • Viral Matrix Proteins / metabolism*


  • EBV-associated membrane antigen, Epstein-Barr virus
  • NF-kappa B
  • Transforming Growth Factor beta1
  • Viral Matrix Proteins