Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease
| Autor: | Sunrui Chen, Meng Li, J. Jasper Deuring, Wenshi Wang, Colin de Haar, C. Janneke van der Woude, Wanlu Cao, Maikel P. Peppelenbosch |
|---|---|
| Přispěvatelé: | Gastroenterology & Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Biopsy Cell Lines Gene Expression Pathology and Laboratory Medicine Inflammatory bowel disease chemistry.chemical_compound 0302 clinical medicine Gene expression Medicine and Health Sciences Organ Cultures Intestinal Mucosa Immune Response Pregnane X receptor Multidisciplinary medicine.diagnostic_test NF-kappa B Pregnane X Receptor Organoids Medicine Cytokines 030211 gastroenterology & hepatology Biological Cultures Signal transduction Anatomy Rifampin Research Article Signal Transduction Colon Science Immunology Surgical and Invasive Medical Procedures Gastroenterology and Hepatology Research and Analysis Methods digestive system 03 medical and health sciences Signs and Symptoms Western blot Diagnostic Medicine Cell Line Tumor medicine Genetics Humans Inflammation business.industry Inflammatory Bowel Disease Biology and Life Sciences NF-κB medicine.disease Inflammatory Bowel Diseases digestive system diseases Gastrointestinal Tract 030104 developmental biology chemistry Caco-2 Cell culture Cancer research Caco-2 Cells business Digestive System |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 10, p e0221924 (2019) PLoS One (print), 14(10):e0221924. Public Library of Science |
| ISSN: | 1932-6203 |
| Popis: | Background The Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best. Methods We stimulate a total of 106 colonic biopsies from 19 Crohn’s disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organoids and various cell culture models (either proficient or genetically deficient with respect to PXR) in vitro with the PXR ligand rifampicin or vehicle. Effects on NF-κB activity are assessed by measuring interleukin-8 (IL-8) and interleukin-1s (IL-1s) mRNA levels by qPCR and in cell culture models by NF-κB reporter-driven luciferase activity and Western blot for signal transduction elements. Results We observe a strict inverse correlation between colonic epithelial PXR levels and NF-κB target gene expression in colonic biopsies from Crohn’s disease patients. PXR, activated by rifampicin, is rate-limiting for mucosal NF-κB activation in IBD. The correlation between colonic epithelial PXR levels and NF-κB target gene expression was also observed in intestinal organoids system. Furthermore, in preclinical in vitro models of intestinal inflammation, including intestinal organoids, genetic inactivation of PXR unleashes NF-κB-dependent signal transduction whereas conversely NF-κB signaling reduces levels of PXR expression. Conclusions Our data indicate that the PXR is a major and clinically relevant antagonist of NF-κB activity in the intestinal epithelial compartment during inflammatory bowel disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |