Tumor necrosis factor-related apoptosis-inducing ligand regulates hallmark features of airways remodeling in allergic airways disease

Am J Respir Cell Mol Biol. 2014 Jul;51(1):86-93. doi: 10.1165/rcmb.2013-0490OC.


Allergic asthma is a complex disease characterized by acute inflammation of the airways that over time leads to the development of significant structural changes termed remodeling. TNF-related apoptosis-inducing ligand (TRAIL) has an important regulatory role in acute allergic airways inflammation through up-regulation of the E3 ubiquitin ligase Midline-1 (MID-1), which limits protein phosphatase 2A (PP2A) activity and downstream dephosphorylation of proinflammatory signaling molecules. The relevance of TRAIL in the development of airways remodeling has yet to be determined. In this study, the lungs of wild-type (WT) BALB/c and Tnfsf10 knockout (TRAIL-/-) mice were chronically exposed to ovalbumin (OVA) for 12 weeks to induce hallmark features of chronic allergic airways disease, including airways hyperreactivity (AHR), subepithelial collagen deposition, goblet cell hyperplasia, and smooth muscle hypertrophy. TRAIL-/- mice were largely protected from the development of AHR and peribronchial eosinophilia and had reduced levels of mast cells in the airways. This correlated with lower levels of cytokines, including IL-4, -5, -10, and -13, and with lower levels of proinflammatory chemokines from cultured cells isolated from the draining lymph nodes. TRAIL-/- mice were also protected from the characteristic features of airways remodeling, including peribronchial fibrosis, smooth muscle hypertrophy, and mucus hypersecretion, which correlated with reduced TGF-β1 levels in the lungs. MID-1 expression was reduced in TRAIL-/- mice and up-regulated in allergic WT mice. Raising PP2A activity using 2-amino-4-(4-heptyloyphenol)-2-methylbutan-1-ol in allergic WT mice reduced eosinophilia, TGF-β1, and peribronchial fibrosis. This study shows that TRAIL promotes airways remodeling in an OVA-induced model of chronic allergic airways disease. Targeting TRAIL and its downstream proinflammatory signaling pathway involving PP2A may be of therapeutic benefit in reducing the hallmark features of airways remodeling observed in chronic allergic airways inflammation.

Keywords: TNF-related apoptosis-inducing ligand; asthma; remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling / drug effects
  • Airway Remodeling / physiology*
  • Animals
  • Apoptosis
  • Blotting, Western
  • Bronchial Hyperreactivity / chemically induced
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / metabolism
  • Bronchial Hyperreactivity / pathology*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mucus / drug effects
  • Mucus / metabolism
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / immunology
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / pathology*
  • Ovalbumin / pharmacology
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • Proteins / genetics
  • Proteins / metabolism
  • Pulmonary Eosinophilia / chemically induced
  • Pulmonary Eosinophilia / immunology
  • Pulmonary Eosinophilia / metabolism
  • Pulmonary Eosinophilia / pathology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • TNF-Related Apoptosis-Inducing Ligand / physiology*
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Ubiquitin-Protein Ligases


  • Cytokines
  • Proteins
  • RNA, Messenger
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Transforming Growth Factor beta1
  • Ovalbumin
  • Mid1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Protein Phosphatase 2