Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease


Autoři: J. Jasper Deuring aff001;  Meng Li aff001;  Wanlu Cao aff001;  Sunrui Chen aff001;  Wenshi Wang aff001;  Colin de Haar aff001;  C. Janneke van der Woude aff001;  Maikel Peppelenbosch aff001
Působiště autorů: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands aff001
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221924

Souhrn

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-1ß (IL-1ß) 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.

Klíčová slova:

Biopsy – Colon – Gastrointestinal tract – Gene expression – Inflammation – Inflammatory bowel disease – Organoids – Caco-2 cells


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2019 Číslo 10

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