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

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dc.contributor.authorCollison, A.
dc.contributor.authorLi, J.
dc.contributor.authorPereira De Siqueira, A.
dc.contributor.authorZhang, J.
dc.contributor.authorToop, H.D.
dc.contributor.authorMorris, J.C.
dc.contributor.authorFoster, P.S.
dc.contributor.authorMattes, J.
dc.date.issued2014
dc.description.abstractAllergic 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 (TRAIL2/2) 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. TRAIL2/2 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. TRAIL2/2 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-b1 levels in the lungs. MID-1 expression was reduced in TRAIL2/2 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-b1, 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.
dc.description.statementofresponsibilityAdam Collison, Junyao Li, Ana Pereira de Siqueira, Jie Zhang, Hamish D. Toop, Jonathan C. Morris, Paul S. Foster, and Joerg Mattes
dc.identifier.citationAmerican Journal of Respiratory Cell and Molecular Biology, 2014; 51(1):86-93
dc.identifier.doi10.1165/rcmb.2013-0490OC
dc.identifier.issn1044-1549
dc.identifier.issn1535-4989
dc.identifier.orcidToop, H.D. [0000-0003-4637-4764]
dc.identifier.urihttps://hdl.handle.net/2440/133867
dc.language.isoen
dc.publisherAmerican Thoracic Society
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1011153
dc.rights© 2014 by the American Thoracic Society
dc.source.urihttps://doi.org/10.1165/rcmb.2013-0490oc
dc.subjectTNF-related apoptosis-inducing ligand; asthma; remodeling
dc.subject.meshMuscle, Smooth
dc.subject.meshMucus
dc.subject.meshAnimals
dc.subject.meshMice, Inbred BALB C
dc.subject.meshMice, Knockout
dc.subject.meshMice
dc.subject.meshBronchial Hyperreactivity
dc.subject.meshPulmonary Eosinophilia
dc.subject.meshUbiquitin-Protein Ligases
dc.subject.meshProteins
dc.subject.meshOvalbumin
dc.subject.meshRNA, Messenger
dc.subject.meshCytokines
dc.subject.meshBlotting, Western
dc.subject.meshImmunoenzyme Techniques
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
dc.subject.meshApoptosis
dc.subject.meshTransforming Growth Factor beta1
dc.subject.meshTNF-Related Apoptosis-Inducing Ligand
dc.subject.meshProtein Phosphatase 2
dc.subject.meshAirway Remodeling
dc.subject.meshReal-Time Polymerase Chain Reaction
dc.titleTumor necrosis factor-related apoptosis-inducing ligand regulates hallmark features of airways remodeling in allergic airways disease
dc.typeJournal article
pubs.publication-statusPublished

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