Consequences of Aryl Hydrocarbon Receptor Activation in Crohn's Disease

Inflammatory bowel disease (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease that typically affects younger persons of a European descent. Many CD patients seek complementary therapies to help alleviate side effects from conventional medicine and/or to relieve symptoms not relieved by conventional therapeutics. The aryl hydrocarbon receptor (AhR) is a cytosolic receptor that when activated can lead to many outcomes including immunosuppression mediated by the protoypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Popular dietary supplements, such as indole-3-carbinol and indirubin, also act as potent AhR agonists and thus may possess the ability to suppress the immune system. We propose to test the central hypothesis that AhR agonists found in the diet have the potential to dampen inflammation associated with CD. The following Specific Aims will be used to test the hypothesis: Specific Aim 1: Examine the role of AhR activation in development and progression of inflammation associated with CD. Specific Aim 2: Investigate the mechanism(s) by which AhR ligands can directly (Dioxin Response Element (DRE)-dependent) and/or indirectly (DRE-independent) exert their effects on gut inflammation. The general experimental theme involves the pre-treatment of an AhR ligand followed by an intrarectal injection of TNBS to induce a CD-like state in mice. After the treatment period, the markers of inflammation to be assessed include colon histology as well as cytokine levels and cell populations in both the colon and surrounding immune tissue. By using AhR-/- mice as proposed in Specific Aim 1, we will establish the importance of AhR activation during the development of gut inflammation in a CD-like condition. Furthermore, in Specific Aim 2, we will determine the involvement of the DRE in the inflammatory response associated with CD following treatment with various AhR ligands using mutant mice (AhRnls/nls, AhRdbd/dbd) that are incapable of activating target genes via conventional DRE binding. PUBLIC HEALTH RELEVANCE: Since there is no known cause of Crohn's disease (CD), a chronic inflammatory state of the gastrointestinal tract that affects millions of Americans, it is essential to elucidate the cellular mechanisms such that its etiology is better understood and new therapeutics can be developed. Dietary components have been suggested to play a role in the pathogenesis of CD so by investigating the role of these in the inflammation associated with CD we hope to contribute to a better understanding of the inflammatory response elicited in CD.