Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Cells. 2022 Feb 6;11(3):563. doi: 10.3390/cells11030563.


Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury (ALI). As ALI is often associated with a cytokine storm, we determined whether pro-inflammatory cytokines modulate the susceptibility of lung cells to necroptosis and which mediators dominate to control necroptosis. In this study, we pretreated/primed mouse primary lung epithelial and endothelial cells with various inflammatory mediators and assessed cell type-dependent responses to different necroptosis inducers and their underlying mechanisms. We found that interferon-γ (IFNγ) as low as 1 ng/mL preferentially promoted necroptosis and accelerated the release of damage-associated molecular patterns from primary alveolar and airway epithelial cells but not lung microvascular endothelial cells. Type-I IFNα was about fifty-fold less effective than IFNγ. Conversely, TNFα or agonists of Toll-like receptor-3 (TLR3), TLR4, TLR7 and TLR9 had a minor effect. The enhanced necroptosis in IFNγ-activated lung epithelial cells was dependent on IFNγ signaling and receptor-interacting protein kinase-3. We further showed that necroptosis effector mixed lineage kinase domain-like protein (MLKL) was predominantly induced by IFNγ, contributing to the enhanced necroptosis in lung epithelial cells. Collectively, our findings indicate that IFNγ is a potent enhancer of lung epithelial cell susceptibility to necroptosis.

Keywords: IFNγ; MLKL; acute lung injury; lung epithelial cells; necroptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Endothelial Cells / metabolism
  • Epithelial Cells / metabolism
  • Interferon-gamma* / metabolism
  • Interferon-gamma* / pharmacology
  • Lung / pathology
  • Mice
  • Necroptosis*
  • Protein Kinases / metabolism


  • Interferon-gamma
  • MLKL protein, mouse
  • Protein Kinases