Toll interacting protein protects bronchial epithelial cells from bleomycin-induced apoptosis

FASEB J. 2020 Aug;34(8):9884-9898. doi: 10.1096/fj.201902636RR. Epub 2020 Jun 28.


Idiopathic pulmonary fibrosis (IPF) is characterized by altered epithelial cell phenotypes, which are associated with myofibroblast accumulation in the lung. Atypical alveolar epithelial cells in IPF express molecular markers of airway epithelium. Polymorphisms within and around Toll interacting protein (TOLLIP) are associated with the susceptibility to IPF and mortality. However, the functional role of TOLLIP in IPF is unknown. Using lung tissues from IPF and control subjects, we showed that expression of TOLLIP gene in the lung parenchyma is globally lower in IPF compared to controls. Lung cells expressing significant levels of TOLLIP include macrophages, alveolar type II, and basal cells. TOLLIP protein expression is lower in the parenchyma of IPF lungs but is expressed in the atypical epithelial cells of the distal fibrotic regions. Using overexpression and silencing approaches, we demonstrate that TOLLIP protects cells from bleomycin-induced apoptosis using primary bronchial epithelial cells and BEAS-2B cells. The protective effects are mediated by reducing mitochondrial reactive oxygen species (ROS) levels and upregulating autophagy. Therefore, global downregulation of the TOLLIP gene in IPF lungs may predispose injured lung epithelial cells to apoptosis and to the development of IPF.

Keywords: TOLLIP; apoptosis; autophagy; basal cells; idiopathic pulmonary fibrosis; lung epithelial cells.

Publication types

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

MeSH terms

  • Antibiotics, Antineoplastic / adverse effects
  • Apoptosis*
  • Autophagy
  • Bleomycin / adverse effects*
  • Bronchi / cytology*
  • Bronchi / drug effects
  • Bronchi / metabolism
  • Epithelial Cells / cytology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis / chemically induced
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology
  • Idiopathic Pulmonary Fibrosis / prevention & control*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Protective Agents*
  • Reactive Oxygen Species / metabolism


  • Antibiotics, Antineoplastic
  • Intracellular Signaling Peptides and Proteins
  • Protective Agents
  • Reactive Oxygen Species
  • TOLLIP protein, human
  • Bleomycin