Back to Search
Start Over
TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis
- Source :
- BMC Pulmonary Medicine, BMC Pulmonary Medicine, Vol 19, Iss 1, Pp 1-11 (2019)
- Publication Year :
- 2019
- Publisher :
- BioMed Central, 2019.
-
Abstract
- © 2019 The Author(s). Background: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has previously been demonstrated to play a pro-inflammatory role in allergic airways disease and COPD through the upregulation of the E3 ubiquitin ligase MID1 and the subsequent deactivation of protein phosphatase 2A (PP2A). Methods: Biopsies were taken from eight IPF patients presenting to the Second Affiliated Hospital of Jilin University, China between January 2013 and February 2014 with control samples obtained from resected lung cancers. Serum TRAIL, MID1 protein and PP2A activity in biopsies, and patients' lung function were measured. Wild type and TRAIL deficient Tnfsf10 -/- BALB/c mice were administered bleomycin to induce fibrosis and some groups were treated with the FTY720 analogue AAL(s) to activate PP2A. Mouse fibroblasts were treated with recombinant TRAIL and fibrotic responses were assessed. Results: TRAIL in serum and MID1 protein levels in biopsies from IPF patients were increased compared to controls. MID1 levels were inversely associated while PP2A activity levels correlated with DLco. Tnfsf10 -/- and mice treated with the PP2A activator AAL(s) were largely protected against bleomycin-induced reductions in lung function and fibrotic changes. Addition of recombinant TRAIL to mouse fibroblasts in-vitro increased collagen production which was reversed by PP2A activation with AAL(s). Conclusion: TRAIL signalling through MID1 deactivates PP2A and promotes fibrosis with corresponding lung function decline. This may provide novel therapeutic targets for IPF.
- Subjects :
- Male
Necrosis
Pulmonary Fibrosis
Respiratory System
TRAIL
TNF-Related Apoptosis-Inducing Ligand
chemistry.chemical_compound
0302 clinical medicine
Fibrosis
Pulmonary fibrosis
030212 general & internal medicine
Protein Phosphatase 2
Aged, 80 and over
Mice, Knockout
Mice, Inbred BALB C
biology
Nuclear Proteins
respiratory system
Middle Aged
3. Good health
Ubiquitin ligase
PP2A
medicine.anatomical_structure
E3 ubiquitin ligase
Microtubule Proteins
Female
Collagen
medicine.symptom
Research Article
Signal Transduction
Pulmonary and Respiratory Medicine
China
Ubiquitin-Protein Ligases
Bleomycin
03 medical and health sciences
Downregulation and upregulation
medicine
Animals
Humans
Aged
lcsh:RC705-779
Lung
business.industry
MID1
Proteins
lcsh:Diseases of the respiratory system
Protein phosphatase 2
medicine.disease
respiratory tract diseases
030228 respiratory system
chemistry
Case-Control Studies
biology.protein
Cancer research
business
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 14712466
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- BMC Pulmonary Medicine
- Accession number :
- edsair.doi.dedup.....9705521a931f985659911a511017f7ec