期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 370, 期 1, 页码 44-+出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.118.255679
关键词
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资金
- Canadian Foundation for Innovation John R. Evans Leaders Fund
- Crohn's Colitis Canada
- Dr. Lloyd Sutherland Investigatorship in IBD/GI Research
- Natural Sciences and Engineering Research Council (NSERC) [RGPIN-2016-03842]
- National Institutes of Health [CA161879, CA222469]
- U.S. Department of Defense [W81XWH-17-1-0479]
- Broad Medical Research Program-Crohn's & Colitis Foundation Investigator Award [262520]
- CIHR Health Challenges in Chronic Disease Signature Initiative [THC-13523]
- Natural Sciences and Engineering Research Council
- Cumming School of Medicine
- Beverly Philips postdoctoral fellowship through the Snyder Institute for Chronic Diseases at the University of Calgary
- Alberta Innovates
- Canadian Association of Gastroenterology/CIHR/Abbvie
- NSERC Discovery Grant [RPGIN-2014-03734]
- Canadian Institutes of Health Research's (CIHR) Canada Research Chair (CRC) program [Tier II CRC in Host-Microbe Interactions and Chronic Disease]
The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that acts as a xenobiotic sensor, responding to compounds of foreign origin, including pharmaceutical compounds, environmental contaminants, and natural products, to induce transcriptional events that regulate drug detoxification and efflux pathways. As such, the PXR is thought to play a key role in protecting the host from xenobiotic exposure. More recently, the PXR has been reported to regulate the expression of innate immune receptors in the intestine and modulate inflammasome activation in the vasculature. In the current study, we report that activation of the PXR in primed macrophages triggers caspase-1 activation and interleukin-1 beta release. Mechanistically, we show that this response is nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3-dependent and is driven by the rapid efflux of ATP and P2X purinoceptor 7 activation following PXR stimulation, an event that involves pannexin-1 gating, and is sensitive to inhibition of Src-family kinases. Our findings identify a mechanism whereby the PXR drives innate immune signaling, providing a potential link between xenobiotic exposure and the induction of innate inflammatory responses.
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