The Epstein-Barr virus latent membrane protein 1 and transforming growth factor--ß1 synergistically induce epithelial--mesenchymal transition in lung epithelial cells.
Am J Respir Cell Mol Biol
; 44(6): 852-62, 2011 Jun.
Article
em En
| MEDLINE
| ID: mdl-20693406
ABSTRACT
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)-ß1 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-ß1. This effect was mirrored in lung epithelial cells infected with EBV expressing LMP1 and cotreated with TGF-ß1. 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-ß1-induced EMT. LMP1 accentuates the TGF-ß1 activation of ERK. Together, these data demonstrate that the presence of EBV-LMP1 in lung epithelial cells synergizes with TGF-ß1 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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas da Matriz Viral
/
Células Epiteliais
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Fator de Crescimento Transformador beta1
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Pulmão
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article