Yong-Guo Zhang1, Rong Lu1, Yinglin Xia1, David Zhou2,3, Elaine Petrof4, Erika C Claud5, Jun Sun1. 1. Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA. 2. Department of Pathology, University of Rochester, Rochester, New York, USA. 3. Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, Missouri, USA. 4. Department of Medicine, GI Diseases Research Unit and Division of Infectious Diseases, Queen's University, Kingston, Ontario, Canada. 5. Department of Pediatrics and Medicine, The University of Chicago, Chicago, Illinois, USA.
Abstract
Background: Vitamin D3 and vitamin D receptor (VDR) are involved in the pathogenesis of inflammatory bowel disease (IBD) and bacterial infection. Claudin-2 is a junction protein that mediates paracellular water transport in epithelia. Elevation of Claudin-2 is associated with active IBD. However, VDR involved in epithelial junctions under inflammation and infection remains largely unknown. We investigated the mechanisms on how VDR and Claudin-2 are related in inflamed states. Methods: Using cultured VDR-/- enteroids, human intestinal epithelial cells, VDR-/- mice with Salmonella- or DSS-colitis, and human IBD samples, we investigated the mechanisms how VDR and Claudin-2 are related in inflamed states. Results: After Salmonella infection had taken place, we observed significantly enhanced Claudin-2 and an increased bacterial invasion and translocation. A lack of VDR regulation led to a robust increase of Claudin-2 at the mRNA and protein levels post-infection. In DSS-treated VDR-/- mice, Claudin-2 was significantly increased. Location and quantification of Claudin-2 protein in the mouse colons treated with DSS also confirmed these results. Inflammatory cytokines were significantly higher in the serum and mRNA levels in intestine, which are known to increase Claudin-2. Furthermore, in inflamed intestine of ulcerative colitis patients, VDR expression was low and Claudin-2 was enhanced. Mechanistically, we identified the enhanced Claudin-2 promoter activity through the binding sites of NF-κB and STAT in inflamed VDR-/- cells. Conclusions: Our studies have identified a new role for intestinal epithelial VDR in regulating barrier functions in the context of infection and inflammation.
Background: Vitamin D3 and vitamin D receptor (VDR) are involved in the pathogenesis of inflammatory bowel disease (IBD) and bacterial infection. Claudin-2 is a junction protein that mediates paracellular water transport in epithelia. Elevation of Claudin-2 is associated with active IBD. However, VDR involved in epithelial junctions under inflammation and infection remains largely unknown. We investigated the mechanisms on how VDR and Claudin-2 are related in inflamed states. Methods: Using cultured VDR-/- enteroids, human intestinal epithelial cells, VDR-/- mice with Salmonella- or DSS-colitis, and human IBD samples, we investigated the mechanisms how VDR and Claudin-2 are related in inflamed states. Results: After Salmonella infection had taken place, we observed significantly enhanced Claudin-2 and an increased bacterial invasion and translocation. A lack of VDR regulation led to a robust increase of Claudin-2 at the mRNA and protein levels post-infection. In DSS-treated VDR-/- mice, Claudin-2 was significantly increased. Location and quantification of Claudin-2 protein in the mouse colons treated with DSS also confirmed these results. Inflammatory cytokines were significantly higher in the serum and mRNA levels in intestine, which are known to increase Claudin-2. Furthermore, in inflamed intestine of ulcerative colitispatients, VDR expression was low and Claudin-2 was enhanced. Mechanistically, we identified the enhanced Claudin-2 promoter activity through the binding sites of NF-κB and STAT in inflamed VDR-/- cells. Conclusions: Our studies have identified a new role for intestinal epithelial VDR in regulating barrier functions in the context of infection and inflammation.
Authors: Rong Lu; Robin M Voigt; Yongguo Zhang; Ikuko Kato; Yinglin Xia; Christopher B Forsyth; Ali Keshavarzian; Jun Sun Journal: Alcohol Clin Exp Res Date: 2017-03-10 Impact factor: 3.455
Authors: Rana Al-Sadi; Dongmei Ye; Michel Boivin; Shuhong Guo; Mariam Hashimi; Lisa Ereifej; Thomas Y Ma Journal: PLoS One Date: 2014-03-24 Impact factor: 3.240
Authors: Cristiano Pagnini; Andrea Picchianti-Diamanti; Vincenzo Bruzzese; Roberto Lorenzetti; Michele Maria Luchetti; Louis Severino Martin Martin; Roberta Pica; Palma Scolieri; Maria Lia Scribano; Costantino Zampaletta; Maria Sole Chimenti; Bruno Lagana Journal: Int J Mol Sci Date: 2021-02-28 Impact factor: 5.923
Authors: Carolina Battistini; Rafael Ballan; Marcos Edgar Herkenhoff; Susana Marta Isay Saad; Jun Sun Journal: Int J Mol Sci Date: 2020-12-31 Impact factor: 5.923
Authors: Cristiano Pagnini; Maria Carla Di Paolo; Maria Giovanna Graziani; Gianfranco Delle Fave Journal: Front Pharmacol Date: 2021-11-24 Impact factor: 5.810
Authors: Caroline M Weight; Simon P Jochems; Hugh Adler; Daniela M Ferreira; Jeremy S Brown; Robert S Heyderman Journal: Front Cell Infect Microbiol Date: 2021-05-25 Impact factor: 5.293