Fra-1/AP-1 Transcription Factor Negatively Regulates Pulmonary Fibrosis In Vivo
Citation: Rajasekaran S, Vaz M, Reddy SP (
Fra-1/AP-1 Transcription Factor Negatively Regulates Pulmonary Fibrosis In Vivo
Subbiah Rajasekaran 0
Michelle Vaz 0
Sekhar P. Reddy 0
Neeraj Vij, Johns Hopkins School of Medicine, United States of America
0 1 Department of Pediatrics, University of Illinois at Chicago , Chicago , Illinois, United States of America, 2 Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University , Baltimore, Maryland , United States of America
The Fra-1/AP-1 transcription factor plays a key role in tumor epithelial cell progression; however, its role in pathogenic lung fibrosis remains unclear. In the present study, using a genetic approach (Fra-1 deficient mice), we have demonstrated a novel regulatory (protective) role for Fra-1 in lung fibrosis. We found greater levels of progressive interstitial fibrosis, characterized by increased levels of inflammation, collagen accumulation, and profibrotic and fibrotic gene expression in the lungs of Fra1D/D mice than in those of Fra-1+/+ mice following bleomycin treatment. Fra-1 knockdown in human lung epithelial cells caused the upregulation of mesenchymal marker N-cadherin, concomitant with a downregulation of the epithelial phenotype marker E-cadherin, under basal conditions and in response to bleomycin and TGF-b1. Furthermore, Fra-1 knockdown caused an enhanced expression of type 1 collagen and the downregulation of collagenase (MMP-1 and MMP13) gene expression in human lung epithelial cells. Collectively, our findings demonstrate that Fra-1 mediates anti-fibrotic effects in the lung through the modulation of proinflammatory, profibrotic and fibrotic gene expression, and suggests that the Fra-1 transcription factor may be a potential target for pulmonary fibrosis, a progressive disorder with poor prognosis and treatment.
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Funding: Funded by the National Institutes of Health (NIH) grants RO1 ES11863, RO1 HL66109, R21 ES18998 (to SPR). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Pulmonary fibrosis is a chronic, progressive disorder that leads
to morbidity and mortality and is associated with poor prognosis
and treatment. This disease is characterized by fibroblast
proliferation, extracellular matrix (ECM) accumulation, and
alterations in parenchymal architecture leading to scar formation
[1], but the exact mechanisms underlying this pathogenic fibrosis
are not completely defined. Increased production of interstitial
collagens as a result of ECM remodeling and protease and
antiprotease imbalance has been implicated in both experimental
(bleomycin-induced) [2] and human pulmonary fibrosis [3]. The
matrix metalloproteinase (MMP) family members regulate ECM
turnover, whereas collagenases (members of MMP subfamily)
cleave the interstitial collagens, types I, II and III under both
physiologic and pathologic conditions. The activities of these
enzymes are controlled at multiple levels, in particular through
the interactions with their specific inhibitors, known as the tissue
inhibitors of metalloproteinases (TIMPs). Thus, a concerted
regulation of both MMP and TIMP expression is critical to
maintaining tissue homeostasis and remodeling during normal
physiological processes such as development and wound healing
[4]. However, the loss of this coordinated regulation of MMP
and TIMP expression has been shown to contributes to the
development and progression of several diseases, including
fibrosis [5,6,7].
The AP-1 transcription factor, mainly comprised of the Jun
(cJun, Jun-B, Jun-D) and Fos (c-Fos, Fos-B, Fra-1, Fra-2) families
of b-ZIP transcription factors, binds to the TPA response element
(TRE, also known as the AP-1 site) of target gene promoters and
regulates their expression in response to various pro-oxidants and
toxicants. These gene products mediate (mitigate or promote)
oxidative stress and inflammatory responses, as well as cell
growth and tumorigenesis [8]. These diverse cellular processes
mediated by AP-1 family members in response to various
physiological and pathogenic stimuli have generally been
attributed to the nature of activation of Jun and Fos family
members, their dimeric composition, and the duration of the
subsequent TRE-mediated induction of genes [9,10]. Many
growth factors and inflammatory cytokines implicated in lung
fibrosis, including the TGF-b1, are known regulators of the AP-1
activity both in vitro and in vivo [10,11]; however, the exact
relevance of Jun and Fos family member activation in
profibrotic stimuli and their contribution to lung fibrosis are largely
undefined. Several studies, including ours, have shown that
ectopic Fra-1 expression upregulates the expression of genes
controlling tissue/cell remodeling, such as MMP-1, MMP-2, and
MMP-9, mainly at the transcriptional level [12,13,14,15,16] (...truncated)