Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo.
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-1(Δ/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.
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Subbiah
S
Rajasekaran
Michelle
M
Vaz
Sekhar P
SP
Reddy
D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000150:complications / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D000099169:Fos-Related Antigen 1
D001761:Bleomycin; D016207:Cytokines; D018836:Inflammation Mediators; D020782:Matrix Metalloproteinases; D016760:Proto-Oncogene Proteins c-fos; D019714:Tissue Inhibitor of Metalloproteinases; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D000099169:Fos-Related Antigen 1