title: Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia.
abstract: IL-10 is a potent anti-inflammatory cytokine that inhibits the production of proinflammatory mediators. Signaling by IL-10 occurs through the IL-10 receptor (IL-10R), which is expressed in numerous cell types, including intestinal epithelial cells (IECs), where it is associated with development and maintenance of barrier function. Guided by an unbiased metabolomics screen, we identified tryptophan (Trp) metabolism as a major modifying pathway in interferon-γ (IFNγ)-dominant murine colitis. In parallel, we demonstrated that IFNγ induction of indoleamine 2,3-dioxygenase 1, an enzyme that catalyzes the conversion of Trp to kynurenine (Kyn), induces IL-10R1 expression. Based on these findings, we hypothesized that IL-10R1 expression on IEC is regulated by Trp metabolites. Analysis of the promoter region of IL-10R1 revealed a functional aryl hydrocarbon response element, which is induced by Kyn in luciferase-based IL-10R1 promoter assays. Additionally, this analysis confirmed that IL-10R1 protein levels were increased in response to Kyn in IEC in vitro. Studies using in vitro wounding assays revealed that Kyn accelerates IL-10-dependent wound closure. Finally, reduction of murine dextran sodium sulfate colitis through Kyn administration correlates with colonic IL-10R1 expression. Taken together, these results provide evidence on the importance of IL-10 signaling in intestinal epithelia and implicate AHR in the regulation of IL-10R1 expression in the colon.
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Lanis
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Alexeev
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: V F
authors.initials: VF
authors.lastname: Curtis
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Kitzenberg
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kao
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Battista
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Gerich
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Glover
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kominsky
authors.affiliation: Mucosal Inflammation Program, Aurora, Colarado, USA.|Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction; D014364:Tryptophan / Q000378:metabolism*; D014945:Wound Healing
chemical_list: C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053709:Interleukin-10 Receptor alpha Subunit; D018336:Receptors, Aryl Hydrocarbon; D016753:Interleukin-10; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D016264:Dextran Sulfate