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Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia
- Source :
- Mucosal immunology
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
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.
- Subjects :
- 0301 basic medicine
colitis
Receptor expression
Interleukin-10 Receptor alpha Subunit
Immunology
Response element
wound healing
Biology
Article
Proinflammatory cytokine
Interferon-gamma
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Animals
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Immunology and Allergy
Intestinal Mucosa
Promoter Regions, Genetic
Receptor
mucosa
Kynurenine
Mice, Knockout
Dextran Sulfate
Tryptophan
Aryl hydrocarbon receptor
metabolomics
Interleukin-10
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
Interleukin 10
030104 developmental biology
Gene Expression Regulation
Receptors, Aryl Hydrocarbon
Biochemistry
chemistry
inflammation
biology.protein
Signal transduction
Signal Transduction
030215 immunology
Subjects
Details
- ISSN :
- 19330219
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Mucosal Immunology
- Accession number :
- edsair.doi.dedup.....1f21863b1e6ccaead6ebef12302401bf