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Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract
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MONTELEONE, IVAN; Rizzo, A; Sarra, M; SICA, GIUSEPPE; SILERI, PIERPAOLO; BIANCONE, LIVIA; MacDonald, T; +2 Authors
MONTELEONE, IVAN; Rizzo, A; Sarra, M; SICA, GIUSEPPE; SILERI, PIERPAOLO; BIANCONE, LIVIA; MacDonald, T; PALLONE, FRANCESCO; MONTELEONE, GIOVANNI;
Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract
The pathogenesis of inflammatory bowel disease (IBD) is believed to involve an altered balance between effector and regulatory T cells. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor that mediates the toxicity of dioxins, controls T-cell responses. We investigated the role of AhR in inflammation and pathogenesis of IBD in humans and mouse models.AhR expression was evaluated in intestinal tissue samples from patients with IBD and controls by real-time polymerase chain reaction (PCR) and flow cytometry. Intestinal lamina propria mononuclear cells (LPMCs) were activated in the presence or absence of the AhR agonist 6-formylindolo(3, 2-b)carbazole (Ficz). Colitis was induced in mice using trinitrobenzene sulfonic acid (TNBS), dextran sulfate sodium (DSS), or T-cell transfer. Mice were given injections of Ficz or the AhR antagonist 2-metyl-2H-pyrazole-3-carboxylic acid; some mice first received injections of a blocking antibody against interleukin (IL)-22. Cytokines were quantified by real-time PCR and flow cytometry.Intestine tissue from patients with IBD expressed significantly less AhR than controls. In LPMCs from patients with IBD, incubation with Ficz reduced levels of interferon gamma (IFN)-γ and up-regulated IL-22. Mice injected with Ficz were protected against TNBS-, DSS-, and T-cell transfer-induced colitis; they had marked down-regulation of inflammatory cytokines and induction of IL-22. Mice given AhR antagonist produced more inflammatory cytokines and less IL-22 and developed a severe colitis. Neutralization of endogenous IL-22 disrupted the protective effect of Ficz on TNBS-induced colitis.AhR is down-regulated in intestinal tissue of patients with IBD; AhR signaling, via IL-22, inhibits inflammation and colitis in the gastrointestinal tract of mice. AhR-related compounds might be developed to treat patients with IBDs.
- Vita-Salute San Raffaele University Italy
- Queen Mary University of London United Kingdom
- University of Rome Tor Vergata Italy
- National Institute for Nuclear Physics Italy
Biopsy, Basic Helix-Loop-Helix Transcription Factor, Severity of Illness Index, Polymerase Chain Reaction, Mice, Receptors, Basic Helix-Loop-Helix Transcription Factors, Inflammation Mediator, Inbred BALB C, Cells, Cultured, FP7, Mice, Inbred BALB C, Cultured, Dextran Sulfate, SP1-Cooperation, Gastroenterology, Middle Aged, Flow Cytometry, Intestine, Up-Regulation, Intestines, Aryl Hydrocarbon, Health, Female, Drug, Inflammation Mediators, Case-Control Studie, Human, Signal Transduction, Adult, Time Factor, Cells, Settore MED/12 - GASTROENTEROLOGIA, Carbazole, Carbazoles, Animals; Humans; Dextran Sulfate; Interleukins; Disease Models, Animal; Inflammatory Bowel Diseases; Biopsy; Mice, Inbred BALB C; Receptors, Aryl Hydrocarbon; Intestines; Adult; Inflammation Mediators; Flow Cytometry; Time Factors; Signal Transduction; T-Lymphocytes; Carbazoles; Severity of Illness Index; Dose-Response Relationship, Drug; Trinitrobenzenesulfonic Acid; Mice; Basic Helix-Loop-Helix Transcription Factors; Polymerase Chain Reaction; Cells, Cultured; Case-Control Studies; Middle Aged; Up-Regulation; Female, Dose-Response Relationship, Animals; Humans; Dextran Sulfate; Interleukins; Disease Models; Animal; Inflammatory Bowel Diseases; Biopsy; Mice; Inbred BALB C; Receptors; Aryl Hydrocarbon; Intestines; Adult; Inflammation Mediators; Flow Cytometry; Time Factors; Signal Transduction; T-Lymphocytes; Carbazoles; Severity of Illness Index; Dose-Response Relationship; Drug; Trinitrobenzenesulfonic Acid; Mice; Basic Helix-Loop-Helix Transcription Factors; Polymerase Chain Reaction; Cells; Cultured; Case-Control Studies; Middle Aged; Up-Regulation; Female, Animals, Humans, European Commission, EC, Dose-Response Relationship, Drug, Animal, Interleukins, Inflammatory Bowel Disease, Interleukin, Inflammatory Bowel Diseases, Disease Models, Animal, T-Lymphocyte, Trinitrobenzenesulfonic Acid, Case-Control Studies, Disease Models
Biopsy, Basic Helix-Loop-Helix Transcription Factor, Severity of Illness Index, Polymerase Chain Reaction, Mice, Receptors, Basic Helix-Loop-Helix Transcription Factors, Inflammation Mediator, Inbred BALB C, Cells, Cultured, FP7, Mice, Inbred BALB C, Cultured, Dextran Sulfate, SP1-Cooperation, Gastroenterology, Middle Aged, Flow Cytometry, Intestine, Up-Regulation, Intestines, Aryl Hydrocarbon, Health, Female, Drug, Inflammation Mediators, Case-Control Studie, Human, Signal Transduction, Adult, Time Factor, Cells, Settore MED/12 - GASTROENTEROLOGIA, Carbazole, Carbazoles, Animals; Humans; Dextran Sulfate; Interleukins; Disease Models, Animal; Inflammatory Bowel Diseases; Biopsy; Mice, Inbred BALB C; Receptors, Aryl Hydrocarbon; Intestines; Adult; Inflammation Mediators; Flow Cytometry; Time Factors; Signal Transduction; T-Lymphocytes; Carbazoles; Severity of Illness Index; Dose-Response Relationship, Drug; Trinitrobenzenesulfonic Acid; Mice; Basic Helix-Loop-Helix Transcription Factors; Polymerase Chain Reaction; Cells, Cultured; Case-Control Studies; Middle Aged; Up-Regulation; Female, Dose-Response Relationship, Animals; Humans; Dextran Sulfate; Interleukins; Disease Models; Animal; Inflammatory Bowel Diseases; Biopsy; Mice; Inbred BALB C; Receptors; Aryl Hydrocarbon; Intestines; Adult; Inflammation Mediators; Flow Cytometry; Time Factors; Signal Transduction; T-Lymphocytes; Carbazoles; Severity of Illness Index; Dose-Response Relationship; Drug; Trinitrobenzenesulfonic Acid; Mice; Basic Helix-Loop-Helix Transcription Factors; Polymerase Chain Reaction; Cells; Cultured; Case-Control Studies; Middle Aged; Up-Regulation; Female, Animals, Humans, European Commission, EC, Dose-Response Relationship, Drug, Animal, Interleukins, Inflammatory Bowel Disease, Interleukin, Inflammatory Bowel Diseases, Disease Models, Animal, T-Lymphocyte, Trinitrobenzenesulfonic Acid, Case-Control Studies, Disease Models
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This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
Citations provided by BIP!popularityPopularity provided by BIP!
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
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This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
Influence provided by BIP!impulseImpulse provided by BIP!
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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