Inflammation in the GI tract can trigger clinical disorders such as Inflammatory bowel disease (IBD), in the form of ulcerative colitis (UC) and Crohn's disease (CD), the precise mechanisms of which are unclear. It is well-established that human IBD is dependent on immunologic, environmental, and genetic factors. It is estimated that there are ~1.4 million individuals that are affected with the disease in the United States. IBD results in over 700,000 hospital visits and 100,000 hospitalizations annually. There are currently few available treatment options for IBD. Indoles, such as diindolylmethane (DIM) and indole-3-carbinol (I3C), found in cruciferous vegetables, have been shown to have anti-tumor effects, while their anti-inflammatory properties have not been well characterized. We have recently made an exciting observation that I3C and DIM can activate aryl hydrocarbon receptor (AhR), and suppress inflammation. We also observed epigenetic modulation including hypomethylation of FoxP3 in activated T cells following treatment with indoles. In the current study, we will test the central hypothesis that treatment with I3c and DIM, activates AhR, leading to reciprocal regulation of proinflammatory T cells versus anti-inflammatory T cells via epigenetic pathways including DNA methylation and histone methylation/acetylation as well as miR induction, leading to suppression of inflammation in the GI tract.
The specific aims are:
Aim 1 : We will test the hypothesis that indoles suppress colonic inflammation through a switch in T cell differentiation from proinflamamtory Th1/Th17 cell responses to anti-inflammatory Th2 and FoxP3+ Tregs through activation of AhR. We will use three mouse models of colitis: DSS, TNBS and Citrobacter rodentium, and determine the role of AhR using AhR KO mice and AhR antagonists.
Aim 2 : We will test the hypothesis that I3C and DIM cause a switch from proinflammatory to anti-inflammatory T cells through epigenetic pathways including DNA methylation, and histone methylation/acetylation by testing the epigenetic signature profiles of key molecules: Foxp3, IL-4, IL-17, IFN-? and transcription factors.
Aim 3 : We will test the hypothesis that microRNAs (miRs) induced by indoles also play a key role in the regulation of T cell differentiation leading to suppression of inflammation: Specifically, we will study the role of miR-190, miR-217, miR-203, miR-320 and miR-494 in the regulation of FoxP3 and IL-17. The CD4+ T cells will be transfected with specific miR mimetics or antagomiRs and target mRNA, transcription factor and cytokines produced will be investigated. Together, the current studies will address how I3C and DIM, used as CAM, can suppress inflammation through activation of epigenetic and miR regulation pathways. Such studies are novel, exciting, and open new avenues for addressing the precise mechanisms of action of CAM modalities.
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