Aryl Hydrocarbon Receptor Activation by TCDD Reduces Inflammation Associated with Crohn's Disease

Abstract

Crohn's disease results from a combination of genetic and environmental factors that trigger an inappropriate immune response to commensal gut bacteria. The aryl hydrocarbon receptor (AhR) is well known for its involvement in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant that affects people primarily through the diet. Recently, TCDD was shown to suppress immune responses by generating regulatory T cells (Tregs). We hypothesized that AhR activation dampens inflammation associated with Crohn's disease. To test this hypothesis, we utilized the 2,4,6-trinitrobenzenesulfonic acid (TNBS) murine model of colitis. Mice were gavaged with TCDD prior to colitis induction with TNBS. Several parameters were examined including colonic inflammation via histological and flow cytometric analyses. TCDD-treated mice recovered body weight faster and experienced significantly less colonic damage. Reduced levels of interleukin (IL) 6, IL-12, interferon-gamma, and tumor necrosis factor-α demonstrated suppression of inflammation in the gut following TCDD exposure. Forkhead box P3 (Foxp3)(egfp) mice revealed that TCDD increased the Foxp3+ Treg population in gut immune tissue following TNBS exposure. Collectively, these results suggest that activation of the AhR by TCDD decreases colonic inflammation in a murine model of colitis in part by generating regulatory immune cells. Ultimately, this work may lead to the development of more effective therapeutics for the treatment of Crohn's disease.

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

“…The AhR is expressed in the gastrointestinal tract, and studies in animal models demonstrate that this receptor and its ligands play an important role in gut health and response to stressors and disease (Kawajiri et al, 2009;Arsenescu et al, 2011;Benson and Shepherd, 2011;Furumatsu et al, 2011;Kiss et al, 2011;Li et al, 2011;Monteleone et al, 2011;Singh et al, 2011;Lee et al, 2012). Loss of the AhR results in formation of colon tumors at the cecum, and this is accompanied by increased expression of b-catenin in the small intestine, whereas wild-type AhR +/+ mice do not develop tumors or overexpress b-catenin (Kawajiri et al, 2009).…”

“…The severity of the effects of 2,4-trinitrobenzene sulfonic acid-induced colitis (which resembles Crohn's disease) in mice was significantly decreased by treatment with the AhR agonists FICZ and TCDD (Benson and Shepherd, 2011), and this was accompanied by suppression of several markers of inflammation. The severity of dextran sodium sulfate-induced colitis in mice was also decreased by the AhR agonists b-naphthoflavone (Furumatsu et al, 2011), TCDD (Benson and Shepherd,201), and FICZ ; in the latter study, the AhR antagonist 2-methyl-2H-pyrazole-3-carboxylic acid enhanced the severity of the colitis .…”

“…The development of AhR 2/2 and tissue-specific AhR knockout mice has been instrumental in showing that this receptor plays an essential role in various tissues and is a critical regulator of inflammation, autoimmune and immune responses and is a potential drug target for treating multiple diseases including cancer (Kerkvliet, 2009;Stevens et al, 2009;Marshall and Kerkvliet, 2010;Busbee et al, 2013;Safe et al, 2013 vegetables play a protective role in mouse models of intestinal cancer and inflammation (Kawajiri et al, 2009;Arsenescu et al, 2011;Benson and Shepherd, 2011;Furumatsu et al, 2011;Kiss et al, 2011;Li et al, 2011;Monteleone et al, 2011;Singh et al, 2011;Lee et al, 2012). Several studies have reported that the gut microbiota produces metabolites that include AhR-active compounds that could potentially modulate AhR-mediated intestinal resiliency and responses to inflammatory stimuli (Li et al, 2009;Bansal et al, 2010;Zelante et al, 2013;Fukumoto et al, 2014;Venkatesh et al, 2014).…”

Aryl Hydrocarbon Receptor Control of Adaptive Immunity

“…Indeed, the administration of certain AhR ligands, including TCDD, the quintessential environmental AhR ligand, leads to the expansion of functional Tregs that arrest the development of experimental autoimmune encephalomyelitis (EAE) (Quintana et al, 2008), experimental autoimmune uveoretinitis (Zhang et al, 2009), colitis (Benson and Shepherd, 2011;Singh et al, 2011b), and spontaneous autoimmune diabetes (Kerkvliet et al, 2009). Some limitations, however, will have to be overcome to translate these findings to the treatment of human autoimmune disorders.…”

Consequences of TCDD treatment on intra-hepatic lymphocytes during liver regeneration

“…Exposure to TCDD has been shown to increase IFNγ production in several model systems (Warren et al, 2000;Sugita-Konishi et al, 2003), while decreasing it in others (Prell et al, 1995;Benson and Shepherd, 2011). Reports describing the effects of TCDD treatment on NK cell activation are equally disparate (Funseth and Ilback, 1992b;Neff-LaFord et al, 2003;Wang et al, 2009), yet provide evidence that these cells may indeed be susceptible to modulation by TCDD treatment.…”