5-Aminosalicylic Acid, A Weak Agonist for Aryl Hydrocarbon Receptor That Induces Splenic Regulatory T Cells

Introduction: 5-Aminosalicylic acid (5-ASA) is widely used as a key drug in inflammatory bowel disease. It has been recently reported that 5-ASA induces CD4 + Foxp3 + regulatory T cells (Tregs) in the colon via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that regulates inflammation. However, the role of 5-ASA as an AhR agonist that induces Tregs in the spleen remains unknown. Methods: In the present study, we investigated these themes using an AhR-mediated transactivation assay and flow cytometry analysis. The experiments were conducted by using DR-EcoScreen cells and C57BL/6 mice. Results: The DR-EcoScreen cell-based transactivation assay revealed that 5-ASA acted as a weak AhR agonist at concentrations of ≥300 μM (1.31–1.45-fold), and that a typical AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), activated AhR at a concentration of 0.1 nM (22.8-fold). In addition, the treatment of mouse splenic cells with 300 μM 5-ASA in a primary culture assay significantly induced CD4+CD25 + Foxp3 + Tregs (control vs. 5-ASA: 9.0% vs. 12.65%, p < 0.05), while 0.1 nM TCDD also showed significant induction of Tregs (control vs. TCDD: 9.0% vs. 14.1%, p < 0.05). Interestingly, this induction was eliminated by co-treatment with an AhR antagonist, CH-223191. Discussion: These results suggest that 5-ASA is a weak agonist of AhR and thereby induces Tregs in spleen cells. Our findings may provide useful insights into the mechanism by which 5-ASA regulates inflammation.

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An endogenous aryl hydrocarbon receptor ligand, ITE, induces regulatory T cells and ameliorates experimental colitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00413.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. G220-G230 ◽

Cited By ~ 13

Author(s):

Jessica D. Abron ◽

Narendra P. Singh ◽

Manoj K. Mishra ◽

Robert L. Price ◽

Mitzi Nagarkatti ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Methyl Ester ◽

Regulatory T Cells ◽

Aryl Hydrocarbon Receptor ◽

Inflammatory Cytokines ◽

Acid Methyl Ester ◽

Aryl Hydrocarbon ◽

Acid Methyl ◽

Inflammatory Bowel

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health care costs. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if a nontoxic ligand of AhR, 2-(1′ H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulfate-induced colitis. Our studies demonstrated that in mice that received ITE treatment in vivo, colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs), and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared with controls. This induction of Tregs was reversed by AhR antagonist treatment in vitro. ITE treatment also increased dendritic cells (CD11c+) and decreased macrophages (F4/80+) from the spleen, MLNs, and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6, and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+T cells and cytokines. Therefore, our work demonstrates that the nontoxic endogenous AhR ligand ITE may serve as a therapeutic modality to treat IBD.NEW & NOTEWORTHY We report the novel finding that activation of the aryl hydrocarbon receptor with the nontoxic ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces regulatory T cells (Tregs) and suppresses inflammatory bowel disease (IBD). Our data suggest that ITE diminishes colitis pathology through induction of Tregs; reduces inflammatory cytokines, inflammation score, and macrophage frequency; and induces DCs resulting in amelioration of colitis. Therefore, nontoxic endogenous ITE promotes the induction of Tregs and may be useful for the treatment of IBD.

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Faculty Opinions recommendation of Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4942963.4875063 ◽

2010 ◽

Author(s):

Rachel R Caspi ◽

Ru Zhou

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Aryl Hydrocarbon Receptor ◽

Regulatory T Cell ◽

Human Type ◽

Aryl Hydrocarbon

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Activation of the Aryl Hydrocarbon Receptor by 10-Cl-BBQ Prevents Insulitis and Effector T Cell Development Independently of Foxp3+ Regulatory T Cells in Nonobese Diabetic Mice

The Journal of Immunology ◽

10.4049/jimmunol.1501789 ◽

2015 ◽

Vol 196 (1) ◽

pp. 264-273 ◽

Cited By ~ 14

Author(s):

Allison K. Ehrlich ◽

Jamie M. Pennington ◽

Xisheng Wang ◽

Diana Rohlman ◽

Sumit Punj ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Aryl Hydrocarbon Receptor ◽

T Cell Development ◽

Diabetic Mice ◽

Effector T Cell ◽

Aryl Hydrocarbon ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice

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From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation

International Journal of Molecular Sciences ◽

10.3390/ijms21217849 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7849

Author(s):

Narendra Prasad Singh ◽

Mitzi Nagarkatti ◽

Prakash Nagarkatti

Keyword(s):

Immune Response ◽

T Cells ◽

Regulatory T Cells ◽

Environmental Chemicals ◽

Suppressor T Cells ◽

Thymic Involution ◽

Halogenated Aromatic Hydrocarbons ◽

Aryl Hydrocarbon ◽

Environmental Sensor

Aryl hydrocarbon receptor (AhR) was identified in the early 1970s as a receptor for the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), which is a member of halogenated aromatic hydrocarbons (HAHs). TCDD was found to be highly toxic to the immune system, causing thymic involution and suppression of a variety of T and B cell responses. The fact that environmental chemicals cause immunosuppression led to the emergence of a new field, immunotoxicology. While studies carried out in early 1980s demonstrated that TCDD induces suppressor T cells that attenuate the immune response to antigens, further studies on these cells were abandoned due to a lack of specific markers to identify such cells. Thus, it was not until 2001 when FoxP3 was identified as a master regulator of Regulatory T cells (Tregs) that the effect of AhR activation on immunoregulation was rekindled. The more recent research on AhR has led to the emergence of AhR as not only an environmental sensor but also as a key regulator of immune response, especially the differentiation of Tregs vs. Th17 cells, by a variety of endogenous, microbial, dietary, and environmental ligands. This review not only discusses how the role of AhR emerged from it being an environmental sensor to become a key immunoregulator, but also confers the identification of new AhR ligands, which are providing novel insights into the mechanisms of Treg vs. Th17 differentiation. Lastly, we discuss how AhR ligands can trigger epigenetic pathways, which may provide new opportunities to regulate inflammation and treat autoimmune diseases.

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