Consequences of Aryl Hydrocarbon Receptor Activation in Crohn's Disease.

Jenna Marie Benson, The University of Montana

Abstract

Activation of the aryl hydrocarbon (AhR), a ligand-activated transcription factor present in many immune cells, can trigger immunosuppressive responses through the generation of regulatory cells. Several AhR ligands exist in the diet including environmental contaminants, such as its prototypical ligand 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), and natural sources, such as indole-3-carbinol (I3C) and indirubin. Crohn's disease, a chronic inflammatory state of the gastrointestinal tract, affects millions worldwide; however, the exact cause is unknown and treatments do not cure the disease. The role of the AhR in mucosal immune responses is not well understood to date so we aimed to understand the consequences of AhR activation in gut inflammatory responses. The overall hypothesis of this project is that AhR agonists found in the diet have the potential to dampen inflammation associated with Crohn's disease. The first goal of this project was to examine the role of AhR activation in the development and progression of colitis using TCDD and the natural ligand I3C. TCDD suppressed TNBS-induced colitis, as demonstrated by the decreased disease severity and dampened inflammation in the gut. TCDD-treated mice exhibited decreased inflammatory mediator production and increased frequency of regulatory cells, both Foxp3+ Tregs and dendritic cells (DCs) in gut immune tissues. In comparison, I3C suppressed disease severity in females but not males. Sex-specific effects on colonic cytokine production and gene expression were observed. The second goal of this project was to define the cellular mechanisms by which AhR ligands elicit their effects on important immune cell populations present in the gut. Therefore, we investigated the immunomodulatory effects of the dietary AhR ligands I3C and indirubin in bone marrow derived DCs (BMDCs). I3C-and indirubin-treated BMDCs upregulated the expression of immunoregulatory genes, such as ALDH1A, IDO, and TGFâ, and also drove the generation of Foxp3+ Tregs. Following LPS stimulation, I3C-and IO-treated BMDCs suppressed the LPS-induced production of TNF-á, IL-1â, IL-6 and IL-12. Anti-inflammatory effects were also observed in intestinal epithelial cells (IECs) treated with AhR ligands. Thus, I3C and indirubin possess immunosuppressive and anti-inflammatory effects in BMDCs and IECs. Taken together, our data demonstrate that the AhR is a therapeutic target that warrants further investigation, as natural AhR ligands may effectively prevent the onset of chronic inflammatory diseases or more effectively induce and maintain remission when combined with conventional medicine.