CFTR dysfunction increases endoglin and TGF-β signaling in airway epithelia
| Autor: | William T. Harris, Namasivayam Ambalavanan, Weifeng Zhang, Masheika L. James, Brian Halloran, Stephanie B. Wall, Changchun Ren, Teodora Nicola, Mark MacEwen, Tatjana Coric, Farruk M. Lutful Kabir |
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| Rok vydání: | 2019 |
| Předmět: |
lung disease
Cystic Fibrosis Physiology Cystic Fibrosis Transmembrane Conductance Regulator 030204 cardiovascular system & hematology Cystic fibrosis Cell Line Signalling Pathways 03 medical and health sciences 0302 clinical medicine Transforming Growth Factor beta Transcription (biology) Physiology (medical) TGF beta signaling pathway TGF‐beta medicine Humans Respiratory Physiology CFTR Child Cells Cultured Original Research Messenger RNA Gene knockdown Lung Chemistry Endoglin respiratory system medicine.disease Molecular biology respiratory tract diseases 3. Good health medicine.anatomical_structure Alveolar Epithelial Cells 030217 neurology & neurosurgery Signal Transduction Transforming growth factor |
| Zdroj: | Physiological Reports |
| ISSN: | 2051-817X |
| DOI: | 10.14814/phy2.13977 |
| Popis: | Endoglin (ENG) regulates signaling by transforming growth factor‐β (TGF‐β), a genetic modifier of cystic fibrosis (CF) lung disease severity. We hypothesized that ENG mediates TGF‐β pathobiology in CF airway epithelia. Comparing CF and non‐CF human lungs, we measured ENG by qPCR, immunoblotting and ELISA. In human bronchial epithelial cell lines (16HBE), we used CFTR siRNA knockdown and functional inhibition (CFTRINH‐172) to connect loss of CFTR to ENG synthesis. Plasmid overexpression of ENG assessed the direct effect of ENG on TGF‐β transcription and signal amplification in 16HBE cells. We found ENG protein to be increased more than fivefold both in human CF bronchoalveolar fluid (BALF) and human CF lung homogenates. ENG transcripts were increased threefold in CF, with a twofold increase in TGF‐β signaling. CFTR knockdown in 16HBE cells tripled ENG transcription and doubled protein levels with corresponding increases in TGF‐β signaling. Plasmid overexpression of ENG alone nearly doubled TGF‐β1 mRNA and increased TGF‐β signaling in 16HBE cells. These experiments identify that loss of CFTR function increases ENG expression in CF epithelia and amplifies TGF‐β signaling. Targeting ENG may offer a novel therapeutic opportunity to address TGF‐β associated pathobiology in CF. |
| Databáze: | OpenAIRE |
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