Fra-1/AP-1 Transcription Factor Negatively Regulates Pulmonary Fibrosis In Vivo

PLOS ONE, Dec 2019

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 Fra-1Δ/Δ 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-β1. Furthermore, Fra-1 knockdown caused an enhanced expression of type 1 collagen and the downregulation of collagenase (MMP-1 and MMP-13) 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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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. - 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)


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Subbiah Rajasekaran, Michelle Vaz, Sekhar P. Reddy. Fra-1/AP-1 Transcription Factor Negatively Regulates Pulmonary Fibrosis In Vivo, PLOS ONE, 2012, 7, DOI: 10.1371/journal.pone.0041611