The Epstein-Barr virus latent membrane protein 1 and transforming growth factor--β1 synergistically induce epithelial--mesenchymal transition in lung epithelial cells.
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.
Sides
Mark D
MD
Department of Medicine, Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Klingsberg
Ross C
RC
Shan
Bin
B
Gordon
Kristin A
KA
Nguyen
Hong T
HT
Lin
Zhen
Z
Takahashi
Takashi
T
Flemington
Erik K
EK
Lasky
Joseph A
JA
D045744:Cell Line, Tumor; D002465:Cell Movement; D004847:Epithelial Cells / Q000166:cytology*; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000473:pathology; D008648:Mesoderm / Q000166:cytology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D014763:Viral Matrix Proteins