title: Role of the xenobiotic receptor in inflammatory bowel disease.
abstract: BACKGROUND
  Gene-environment interplay modulates inflammatory bowel diseases (IBD). Dioxin-like compounds can activate the aryl hydrocarbon receptor (AhR) and alter macrophage function as well as T-cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD.
  
  
  METHODS
  Dextran sulfate sodium (DSS) colitis was induced in C57BL/6 AhR null mice (AhR(-/-) ), heterozygous mice (AhR(-/+) ), and their wildtype (WT) littermates. Clinical and morphopathological parameters were used to compare the groups.
  
  
  METHODS
  AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls.
  
  
  RESULTS
  AhR(-/-) mice died before the end of the treatment. However, AhR(-/+) mice exhibited decreased disease activity compared to WT mice. The AhR(-/+) mice expressed less proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) (6.1- versus 15.7-fold increase) and IL17 (23.7- versus 67.9-fold increase) and increased antiinflammatory IL-10 (2.3-fold increase) compared with the AhR(+/+) mice in the colon. Colonic macrophage infiltration was attenuated in the AhR(-/+) group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 -19.9, and IL8- 10-fold increase).
  
  
  CONCLUSIONS
  Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking, or administration of AhR antagonists could be viable strategies for the treatment of IBD.
authors.affiliation: Division of Digestive Diseases and Nutrition, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Razvan
authors.initials: R
authors.lastname: Arsenescu
authors.forename: Violeta
authors.initials: V
authors.lastname: Arsenescu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
authors.forename: Munira
authors.initials: M
authors.lastname: Nasser
authors.forename: Razvan
authors.initials: R
authors.lastname: Melinte
authors.forename: R W Cameron
authors.initials: RW
authors.lastname: Dingle
authors.forename: Hollie
authors.initials: H
authors.lastname: Swanson
authors.forename: Willem J
authors.initials: WJ
authors.lastname: de Villiers
mesh_terms: D052242:Adiponectin / Q000276:immunology / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001706:Biopsy; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015262:Xenobiotics / Q000276:immunology / Q000378:metabolism
chemical_list: D052242:Adiponectin; D051792:Basic Helix-Loop-Helix Proteins; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; C111235:AHR protein, human; C499919:Adipoq protein, mouse; C484722:Ahr protein, mouse