NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR-IL-1R signalling axis
| Autor: | Xiu-Ming Li, Jian-Ming Li, Yuan-Yuan Zhao, Hua Wu, Xindao Zhang, Jing-Ru Wang, Yan-Bing Guo, Xiao-kun Zhang, Fuquan Jiang, Wen-Juan Gan, Xing-Xing Lu, Xiao-Shun He, Yao Liu |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Nerve growth factor IB business.industry medicine.medical_treatment Regulator Genome-wide association study Inflammation medicine.disease Ulcerative colitis Inflammatory bowel disease digestive system diseases Pathology and Forensic Medicine 03 medical and health sciences 030104 developmental biology Cytokine Immunology Medicine medicine.symptom Colitis business |
| Zdroj: | The Journal of Pathology. 238:457-469 |
| ISSN: | 0022-3417 |
| DOI: | 10.1002/path.4670 |
| Popis: | Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD. |
| Databáze: | OpenAIRE |
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