ArticlePloS one2013
The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 53 citations in OpenAlex.
- A randomized controlled trial of precision bezlotoxumab treatment for Clostridioides difficile infection.Cell reports. Medicine · 2026Trial
- High-fat diet-derived metabolite uridine diphosphate (UDP) impairs epithelial regeneration by P2YGut microbes · 2026Article
- Targeting PPARγ-NF-κB: (+)-catechin reversesFuture microbiology · 2026Article
- Modeling Clostridioides difficile toxin pathogenesis and antiserum protection in an immunocompetent intestine-on-chip platform.Scientific reports · 2026Article
- The swine IsoLoop model of the gut host-microbiota interface enables intra-animal treatment comparisons to advance 3R principles.Gut microbes · 2025Article
- Exploring the Toxin-Mediated Mechanisms inMicroorganisms · 2024Review
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- A leaky human colon model reveals uncoupled apical/basal cytotoxicity in earlyAmerican journal of physiology. Gastrointestinal and liver physiology · 2023Article
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- Cytotoxic synergism ofWorld journal of gastroenterology · 2023Review
- Article
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- RNA-seq reveals a novel porcine lncRNA MPHOSPH9-OT1 induces CXCL8/IL-8 expression in ETEC infected IPEC-J2 cells.Frontiers in cellular and infection microbiology · 2022Article
- Invisible steps for a global endemy: molecular strategies adopted byTherapeutic advances in gastroenterology · 2021Review
- A Novel, Orally Delivered Antibody Therapy and Its Potential to PreventFrontiers in microbiology · 2020Article
- TPL2 Is a Key Regulator of Intestinal Inflammation in Clostridium difficile Infection.Infection and immunity · 2018Article
- Clostridium difficile toxins A and B decrease intestinal SLC26A3 protein expression.American journal of physiology. Gastrointestinal and liver physiology · 2018Article
- Cysteine Protease-Mediated Autocleavage ofCellular and molecular gastroenterology and hepatology · 2018Article
- The role of toxins in Clostridium difficile infection.FEMS microbiology reviews · 2017Review
- Cytokines Are Markers of the Clostridium difficile-Induced Inflammatory Response and Predict Disease Severity.Clinical and vaccine immunology : CVI · 2017Article
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
C. difficile is a Gram-positive spore-forming anaerobic bacterium that is the leading cause of nosocomial diarrhea in the developed world. The pathogenesis of C. difficile infections (CDI) is driven by toxin A (TcdA) and toxin B (TcdB), secreted factors that trigger the release of inflammatory mediators and contribute to disruption of the intestinal epithelial barrier. Neutrophils play a key role in the inflammatory response and the induction of pseudomembranous colitis in CDI. TcdA and TcdB alter cytoskeletal signaling and trigger the release of CXCL8/IL-8, a potent neutrophil chemoattractant, from intestinal epithelial cells; however, little is known about the surface receptor(s) that mediate these events. In the current study, we sought to assess whether toxin-induced CXCL8/IL-8 release and barrier dysfunction are driven by the activation of the P2Y6 receptor following the release of UDP, a danger signal, from intoxicated Caco-2 cells. Caco-2 cells express a functional P2Y6 receptor and release measurable amounts of UDP upon exposure to TcdA/B. Toxin-induced CXCL8/IL-8 production and release were attenuated in the presence of a selective P2Y6 inhibitor (MRS2578). This was associated with inhibition of TcdA/B-induced activation of NFκB. Blockade of the P2Y6 receptor also attenuated toxin-induced barrier dysfunction in polarized Caco-2 cells. Lastly, pretreating mice with the P2Y6 receptor antagonists (MSR2578) attenuated TcdA/B-induced inflammation and intestinal permeability in an intrarectal toxin exposure model. Taken together these data outline a novel role for the P2Y6 receptor in the induction of CXCL8/IL-8 production and barrier dysfunction in response to C. difficile toxin exposure and may provide a new therapeutic target for the treatment of CDI.
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