Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 44, Issue 6, Pages 852-862Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2009-0232OC
Keywords
latent membrane protein 1; transforming growth factor-beta 1; epithelial-mesenchymal transition; idiopathic pulmonary fibrosis; Epstein-Barr virus
Funding
- National Institutes of Health [RO1HL083901]
- Louisiana Board of Regents Louisiana [(2008-10)-RD-A-26]
- Louisiana Board of Regents RSGS [LEQSF (2006-11)GF06]
- National Institutes of Health (NIH)
- InterMune
- Novartis
- Merck Banyu
- Fuji Film
- Oncomics
- Ministry of Education, Culture, Sports, Science and Technology (Japanese government)
- Smoking Research Foundation
- Grants-in-Aid for Scientific Research [21249037, 22134005] Funding Source: KAKEN
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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)-beta 1 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-alpha 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-beta 1. This effect was mirrored in lung epithelial cells infected with EBV expressing LMP1 and cotreated with TGF-beta 1. LMP1 pro-EMT signaling was identified, and occurs primarily through the nuclear factor-kappa B 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-beta 1-induced EMT. LMP1 accentuates the TGF-beta 1 activation of ERK. Together, these data demonstrate that the presence of EBV-LMP1 in lung epithelial cells synergizes with TGF-beta 1 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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