Document Detail


The Epstein-Barr virus latent membrane protein 1 and transforming growth factor--β1 synergistically induce epithelial--mesenchymal transition in lung epithelial cells.
MedLine Citation:
PMID:  20693406     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Mark D Sides; Ross C Klingsberg; Bin Shan; Kristin A Gordon; Hong T Nguyen; Zhen Lin; Takashi Takahashi; Erik K Flemington; Joseph A Lasky
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-08-06
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  44     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-09     Completed Date:  2011-08-23     Revised Date:  2012-09-24    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  852-62     Citation Subset:  IM    
Affiliation:
Department of Medicine, Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Tumor
Cell Movement
Epithelial Cells / cytology*
Epithelial-Mesenchymal Transition
Fibrosis / pathology
Herpesvirus 4, Human / metabolism
Humans
Lung / cytology*,  pathology
Mesoderm / cytology
Models, Biological
NF-kappa B / metabolism
Signal Transduction
Transforming Growth Factor beta1 / metabolism*
Viral Matrix Proteins / metabolism*
Grant Support
ID/Acronym/Agency:
R01 CA138268-04/CA/NCI NIH HHS; R01HL083901/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/EBV-associated membrane antigen, Epstein-Barr virus; 0/NF-kappa B; 0/Transforming Growth Factor beta1; 0/Viral Matrix Proteins
Comments/Corrections

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