In well-differentiated primary human bronchial epithelial cells, TGF- β 1 and TGF- β 2 induce expression of furin

Am J Physiol Lung Cell Mol Physiol. 2021 Feb 1;320(2):L246-L253. doi: 10.1152/ajplung.00423.2020. Epub 2020 Nov 11.


The COVID-19 pandemic is an ongoing threat to public health. Since the identification of COVID-19, the disease caused by SARS-CoV-2, no drugs have been developed to specifically target SARS-CoV-2. To develop effective and safe treatment options, a better understanding of cellular mechanisms underlying SARS-CoV-2 infection is required. To fill this knowledge gap, researchers require reliable experimental systems that express the host factor proteins necessary for the cellular entry of SARS-CoV-2. These proteins include the viral receptor, angiotensin-converting enzyme 2 (ACE2), and the proteases, transmembrane serine protease 2 (TMPRSS2) and furin. A number of studies have reported cell-type-specific expression of the genes encoding these molecules. However, less is known about the protein expression of these molecules. We assessed the suitability of primary human bronchial epithelial (HBE) cells maintained in an air-liquid interface (ALI) as an experimental system for studying SARS-CoV-2 infection in vitro. During cellular differentiation, we measured the expression of ACE2, TMPRSS2, and furin over progressive ALI days by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence staining. We also explored the effect of the fibrotic cytokine TGF-β on the expression of these proteins in well-differentiated HBE cells. Like ACE2, TMPRSS2 and furin proteins are localized in differentiated ciliated cells, as confirmed by immunofluorescence staining. These data suggest that well-differentiated HBE cells maintained in ALI are a reliable in vitro system for investigating cellular mechanisms of SARS-CoV-2 infection. We further identified that the profibrotic mediators, TGF-β1 and TGF-β2, increase the expression of furin, which is a protease required for the cellular entry of SARS-CoV-2.

Keywords: ACE2; COVID-19; SARS-CoV-2; TGF-β; TMPRSS2; furin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Bronchi / cytology
  • Bronchi / drug effects
  • Bronchi / metabolism*
  • COVID-19 / etiology*
  • Cell Differentiation
  • Cells, Cultured
  • Disease Susceptibility
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Furin / genetics
  • Furin / metabolism*
  • Gene Expression / drug effects
  • Host Microbial Interactions / drug effects
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / physiology
  • Humans
  • Models, Biological
  • Pandemics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • SARS-CoV-2* / pathogenicity
  • SARS-CoV-2* / physiology
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • Transforming Growth Factor beta2 / metabolism*
  • Transforming Growth Factor beta2 / pharmacology
  • Virus Internalization


  • RNA, Messenger
  • TGFB1 protein, human
  • TGFB2 protein, human
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • FURIN protein, human
  • Furin