ROLE OF NATURAL INDOLES IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
Nagarkatti Mitzi, Dep. Dir., Sc Cancer Center
University Of South Carolina At Columbiacity: Columbia country: United States (us)
Grant 1R01AT006888-01 from National Center For Complementary & Alternative Medicine
Abstract: There are over 80 different autoimmune diseases that are debilitating against which currently there is no cure. Thus, patients resort to complementary and alternative medicine (CAM) to find relief from pain and inflammation. Multiple Sclerosis (MS) is one such autoimmune disease that affects ~350,000-500,000 people in the US. It is a chronic disease characterized by inflammation in the central nervous system that results in neuron demyelination leading to paralysis. Dietary indoles including indole-3-carbinol (I3C) found in cruciferous vegetables such as cauliflower, cabbage and Brussels sprouts, as well as its derivative, diindolylmethane (DIM) have also been known for their health benefits and for their anti-cancer properties. Interestingly, these compounds can bind to the aryl hydrocarbon receptor (AhR), which is well characterized as a transcription factor that regulates xenobiotic metabolism. Also, recent studies suggested that AhR may also regulate certain important immune functions such as T cell differentiation. We have made an exciting observation that dietary indoles such as DIM can completely suppress the clinical disease in an experimental model of MS known as Experimental Autoimmune Encephalomyelitis (EAE). In the current study, we will test the central hypothesis that treatment with these naturally- occurring indoles is effective against induction and progression of EAE through a central pathway of activation of AhR, leading to suppression of proinflammatory Th1/Th17cells and induction of T regs/Th2 cells via epigenetic regulatory mechanisms such as DNA methylation and miRNA dysregulation that block neuroinflammation. To this end, we will test the following aims In aim 1, we will examine whether treatment with indoles such as I3C or DIM leads to decreased neuroinflammation by downregulation of Th1 and Th17 cell responses against myelin antigens and upregulation of Th2 and FoxP3+ Tregs. We will test whether activation of AhR by these indoles leads to dysregulation in the Th/Treg cell responses using AhR knock out (KO) mice. In aim 2, we will test the central hypothesis that indoles facilitate Th17 to Treg switch in EAE mice by DNA hypomethylation of Foxp3 gene promoter while silencing the Th17 activity by hypermethylation of IL-17 promoters. Lastly, in aim 3, we will test the hypothesis that administration of these indoles triggers dysregulation in the expression of microRNA-466i and microRNA-325 that leads to increased polarization of Tregs and decreased differentiation of T17 cells. The current study investigates the mechanism of action of plant-derived indoles used as dietary supplements, specifically addressing the role of AhR activation in the regulation of inflammation. These studies should provide novel insights into the basic mechanisms through which plant indoles exhibit anti- inflammatory properties so that they can be used against a wide range of autoimmune and inflammatory diseases. Cruciferous vegetables are good source of indoles that are used as a dietary supplement to promote health and prevent cancer. We have shown that they activate AhR receptor which can lead to suppression of inflammation and autoimmune disease. The current study will further characterize the mechanism of action of such indoles and how they can be used to treat an experimental model of multiple sclerosis
Keywords: Address; Adjuvant; Adverse effects; Affect; Algorithms; Animal Model; Anti-inflammatory; Anti-Inflammatory Agents; Antigens; Aryl Hydrocarbon Receptor; aryl hydrocarbon receptor ligand; Autoantigens; Autoimmune Diseases; Autoimmune Process; base; Binding (Molecular Function); Broccoli - dietary; Cabbage - dietary; Cauliflower; Cells; Chinese Traditional Medicine; Chronic Disease; Clinical; Complementary and alternative medicine; Computer Simulation; cruciferous vegetable; cytokine; Data; Demyelinations; Development; Dietary Indole; Dietary Supplements; diindolylmethane; Dioxins; Disease; disorder control; DNA; DNA Methylation; Down-Regulation; effective therapy; Elements; Endothelial Cells; Epigenetic Process; Evaluation; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Models; Gene Expression; Gene Targeting; Generations; Genes; Genetic Transcription; Health; Health Benefit; Hypermethylation; immune function; Immunosuppressive Agents; In Vitro; indigo dye; indirubin; Indole-3-Carbinol; Indoles; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; injury prevention; insight; Interferons; Interleukin-17; Interleukin-4; Knockout Mice; Lead; Malignant Neoplasms; Mediating; MicroRNAs; Molecular Profiling; Multiple Sclerosis; Mus; Myelin; Neuraxis; neuroinflammation; Neurons; novel; oligodendrocyte-myelin glycoprotein; Pain; Paralysed; Pathway interactions; Patients; Pharmaceutical Preparations; Plants; Play; prevent; Prevention; Promoter Regions (Genetics); Promotor (Genetics); Property; receptor; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Resort; response; Role; Source; T cell differentiation; T cell response; T-Lymphocyte; Testing; Th2 Cells; transcription factor; Transcriptional Regulation; Transfection; treatment strategy; tumor; Up-Regulation (Physiology); Validation; Xenobiotic Metabolism
Relevance: Cruciferous vegetables are good source of indoles that are used as a dietary supplement to promote health and prevent cancer. We have shown that they activate AhR receptor which can lead to suppression of inflammation and autoimmune disease. The current study will further characterize the mechanism of action of such indoles and how they can be used to treat an experimental model of multiple sclerosis
Project start date: 2011-08-01
Project end date: 2016-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-AT-11-001
1R01AT006888-01 (2011): $411000
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Nagarkatti Mitzi
Nagarkatti Mitzi
University Of South Carolina At Columbiacity: Columbia country: United States (us)
Grant 5R01ES019313-03 from National Institute Of Environmental Health Sciences
Keywords: Age; American; Antigens; Apoptosis; Atrophic; Autoantigens; Autoimmune Diseases; Autoimmunity; Benign; Binding (Molecular Function); cancer type; CD8B1 gene; Cell Communication; Chemicals; Child; Daughter; Development; Diethylstilbestrol; Disease; Elements; Endocrine Disruptors; Environment; Environmental Estrogen; Estradiol; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Exposure to; feeding; Female; Fetal Thymic Organ Culture; Food; Generations; Genes; H-Y Antigen; Health; Hormone replacement therapy; Immune; Immune system; Immune System Diseases; immunoregulation; immunotoxicity; in utero; In Vitro; in vivo; Incidence; Induction of Apoptosis; Infection; insight; Lead; Life; Lifetime Risk; Link; Livestock; Lymphoma; male; malignant breast neoplasm; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; men; Menopausal Symptom; MHC Class I Genes; Mothers; Mus; Newborn Infant; novel; Nuclear; nuclear factors of activated T-cells; offspring; ovarian neoplasm; Pesticides; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Phytoestrogens; Plants; Postmenopause; postnatal; Predisposition; Pregnancy; Premature Birth; prenatal; prenatal exposure; prevent; Prevention; public health relevance; pup; Regulation; Reporting; reproductive; Research; response; Risk; Role; Son; soy; Spontaneous abortion; Stromal Cells; surfactant; T cell differentiation; T-Cell Receptor; T-Lymphocyte; Testing; thymocyte; Thymus Gland; Time; Toxic effect; transcription factor; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; tumor; Tumor Necrosis Factor Ligand Superfamily Member 6; Uterine Cancer; Woman; xenoestrogen
Relevance: There has been a high incidence of cancers as well as autoimmune diseases observed in women who were prescribed during pregnancy, a synthetic estrogen known as diethylstibestrol, as well as in their sons and daughters. Postmenopausal women administered estrogens in hormone replacement therapy, as well as, several chemicals found in the environment and foods act as estrogens causing significant health problems. Thus, our studies are aimed at providing insights into the mechanism by which estrogens mediate their toxic effects on the immune system, thereby leading to the development of strategies for their prevention and treatment
Project start date: 2010-01-08
Project end date: 2014-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01ES019313-03 (2012): $274651