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The Pregnane X Receptor Attenuates Cytokine‐Induced Intestinal Epithelial Barrier Dysfunction, an Effect Associated With Inhibition of JNK Activation and Enhanced Autophagy
Author(s) -
Garg Aditya,
Alston Laurie,
Erickson Sarah,
Hirota Simon
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.854.3
Subject(s) - pregnane x receptor , barrier function , autophagy , microbiology and biotechnology , chemistry , inflammation , western blot , apoptosis , proinflammatory cytokine , receptor , tumor necrosis factor alpha , biology , immunology , transcription factor , biochemistry , nuclear receptor , gene
The role of the innate immune system in sensing the microbiota is well established, but little is known about how microbial metabolites interact with host tissues in the gut. Recently, the pregnane X receptor (PXR) was identified as a sensor for microbial metabolites that regulates intestinal epithelial permeability. Interestingly, mutations in NR1I2 , the gene that encodes the PXR, have been linked to Crohn's disease (CD) and ulcerative colitis (UC), and in animal models, PXR activation attenuates intestinal inflammation and barrier dysfunction. In the current study, we sought to assess the mechanisms through which the PXR preserves barrier function during inflammatory stress. To study barrier function, Caco‐2 cells were grown for 14 days on Transwell plates and FITC‐dextran flux assays performed. Cells were pretreated with PXR agonists (rifaximin and SR12813; 10 µM for 1 hr) and then challenged with TNFα/IFNɣ (10 ng/mL/10 ng/mL; basolateral compartment), for 24 hrs. The activity of JNK, the induction of autophagy and apoptosis were assessed by western blot, and the localization of ZO‐1 was evaluated by immunostaining. PXR activation attenuated TNFα/IFNɣ‐induced barrier disruption, an effect that was associated with reduced JNK activity and enhanced autophagy. Interestingly, PXR activation did not inhibit TNFα/IFNɣ‐induced apoptosis, but attenuated ZO‐1 relocalization. Our data indicate that PXR activation preserves barrier function during inflammatory stress, highlighting a novel role for the PXR in the regulation of intestinal mucosal homeostasis. These data provide support for the development of agents that target the PXR to treat CD and UC.