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PAI-1 augments mucosal damage in colitis
- Source :
- Science translational medicine. 11(482)
- Publication Year :
- 2018
-
Abstract
- There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti-tumor necrosis factor (TNF), and identify new therapeutic targets. In this study, we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in patients with IBD. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation. Functionally, PAI-1 and its direct target, the fibrinolytic protease tissue plasminogen activator (tPA), played an important role in regulating intestinal inflammation. Intestinal epithelial cells produced tPA, which was protective against chemical and mechanical-mediated colonic injury in mice. In contrast, PAI-1 exacerbated mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-β, whereas the inhibition of PAI-1 reduced both mucosal damage and inflammation. This study identifies an immune-coagulation gene axis in IBD where elevated PAI-1 may contribute to more aggressive disease.
- Subjects :
- 0301 basic medicine
Necrosis
Transcription, Genetic
Colon
Inflammation
Inflammatory bowel disease
Tissue plasminogen activator
Severity of Illness Index
Article
Transcriptome
Small Molecule Libraries
03 medical and health sciences
Biological Factors
Mice
0302 clinical medicine
Citrobacter
Transforming Growth Factor beta
Plasminogen Activator Inhibitor 1
medicine
Humans
Animals
Colitis
Intestinal Mucosa
Blood Coagulation
Cell Proliferation
business.industry
Interleukin-17
General Medicine
medicine.disease
Inflammatory Bowel Diseases
030104 developmental biology
Tissue Plasminogen Activator
Cancer research
Cytokines
Th17 Cells
030211 gastroenterology & hepatology
Tumor necrosis factor alpha
medicine.symptom
business
Plasminogen activator
medicine.drug
Subjects
Details
- ISSN :
- 19466242
- Volume :
- 11
- Issue :
- 482
- Database :
- OpenAIRE
- Journal :
- Science translational medicine
- Accession number :
- edsair.doi.dedup.....00c7d36d2505a2183f38b95f4fc4f7ca