Journal Article
. 2017 Jul; 12(6):e0180321.
doi: 10.1371/journal.pone.0180321.

Indole-3-carbinol, a plant nutrient and AhR-Ligand precursor, supports oral tolerance against OVA and improves peanut allergy symptoms in mice

Christiane Hammerschmidt-Kamper 1 Daniel Biljes 1 Katja Merches 1 Irina Steiner 2 Thomas Daldrup 2 Marianne Bol-Schoenmakers 3 Raymond H H Pieters 3 Charlotte Esser 1 
  • PMID: 28666018
  •     66 References
  •     12 citations


In general, dietary antigens are tolerated by the gut associated immune system. Impairment of this so-called oral tolerance is a serious health risk. We have previously shown that activation of the ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) by the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects both oral tolerance and food allergy. In this study, we determine whether a common plant-derived, dietary AhR-ligand modulates oral tolerance as well. We therefore fed mice with indole-3-carbinole (I3C), an AhR ligand that is abundant in cruciferous plants. We show that several I3C metabolites were detectable in the serum after feeding, including the high-affinity ligand 3,3´-diindolylmethane (DIM). I3C feeding robustly induced the AhR-target gene CYP4501A1 in the intestine; I3C feeding also induced the aldh1 gene, whose product catalyzes the formation of retinoic acid (RA), an inducer of regulatory T cells. We then measured parameters indicating oral tolerance and severity of peanut-induced food allergy. In contrast to the tolerance-breaking effect of TCDD, feeding mice with chow containing 2 g/kg I3C lowered the serum anti-ovalbumin IgG1 response in an experimental oral tolerance protocol. Moreover, I3C feeding attenuated symptoms of peanut allergy. In conclusion, the dietary compound I3C can positively influence a vital immune function of the gut.

Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis.
Anatoly A Soshilov, Michael S Denison.
Mol Cell Biol, 2014 Mar 05; 34(9). PMID: 24591650    Free PMC article.
CTLA-4 signaling regulates the intensity of hypersensitivity responses to food antigens, but is not decisive in the induction of sensitization.
Femke van Wijk, Sanne Hoeks, +5 authors, Raymond Pieters.
J Immunol, 2004 Dec 22; 174(1). PMID: 15611239
Retinal dehydrogenase gene expression in stomach and small intestine of rats during postnatal development and in vitamin A deficiency.
P V Bhat.
FEBS Lett, 1998 May 23; 426(2). PMID: 9599020
Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis.
Ada Yeste, Meghan Nadeau, +2 authors, Francisco J Quintana.
Proc Natl Acad Sci U S A, 2012 Jun 30; 109(28). PMID: 22745170    Free PMC article.
Highly Cited.
3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways.
Michael Rouse, Roshni Rao, Mitzi Nagarkatti, Prakash S Nagarkatti.
J Pharmacol Exp Ther, 2014 Jun 06; 350(2). PMID: 24898268    Free PMC article.
The aryl hydrocarbon receptor: multitasking in the immune system.
Brigitta Stockinger, Paola Di Meglio, Manolis Gialitakis, João H Duarte.
Annu Rev Immunol, 2014 Mar 25; 32. PMID: 24655296
Highly Cited. Review.
Type II collagen oral tolerance; mechanism and role in collagen-induced arthritis and rheumatoid arthritis.
Kyung-Su Park, Min-Jung Park, +5 authors, Ho-Youn Kim.
Mod Rheumatol, 2009 Aug 22; 19(6). PMID: 19697097
FICZ, a tryptophan photoproduct, suppresses pulmonary eosinophilia and Th2-type cytokine production in a mouse model of ovalbumin-induced allergic asthma.
Kyu-Tae Jeong, Sung-Jun Hwang, Gap-Soo Oh, Joo-Hung Park.
Int Immunopharmacol, 2012 May 09; 13(4). PMID: 22561122
A comparison of the individual and collective effects of four glucosinolate breakdown products from brussels sprouts on induction of detoxification enzymes.
R Staack, S Kingston, M A Wallig, E H Jeffery.
Toxicol Appl Pharmacol, 1998 Mar 26; 149(1). PMID: 9512722
Toward understanding the role of aryl hydrocarbon receptor in the immune system: current progress and future trends.
Hamza Hanieh.
Biomed Res Int, 2014 Feb 15; 2014. PMID: 24527450    Free PMC article.
A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals.
Deanna M Minich, Jeffrey S Bland.
Nutr Rev, 2007 Jul 04; 65(6 Pt 1). PMID: 17605302
Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.
Cheng-Ming Sun, Jason A Hall, +4 authors, Yasmine Belkaid.
J Exp Med, 2007 Jul 11; 204(8). PMID: 17620362    Free PMC article.
Highly Cited.
Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis.
Arthur Mortha, Aleksey Chudnovskiy, +4 authors, Miriam Merad.
Science, 2014 Mar 15; 343(6178). PMID: 24625929    Free PMC article.
Highly Cited.
Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells.
I D Iliev, I Spadoni, +7 authors, M Rescigno.
Gut, 2009 Jul 03; 58(11). PMID: 19570762
Highly Cited.
6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells.
Rodica P Bunaciu, Andrew Yen.
Mol Cancer, 2013 May 10; 12. PMID: 23656719    Free PMC article.
Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator-dependent system in gut.
Shinji Ito, Chi Chen, +2 authors, Frank J Gonzalez.
J Clin Invest, 2007 Jul 04; 117(7). PMID: 17607366    Free PMC article.
Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans.
Elin Jaensson, Heli Uronen-Hansson, +8 authors, William W Agace.
J Exp Med, 2008 Aug 20; 205(9). PMID: 18710932    Free PMC article.
Highly Cited.
Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor.
Francisco J Quintana, Alexandre S Basso, +6 authors, Howard L Weiner.
Nature, 2008 Mar 26; 453(7191). PMID: 18362915
Highly Cited.
Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation.
Ying Li, Silvia Innocentin, +5 authors, Marc Veldhoen.
Cell, 2011 Oct 18; 147(3). PMID: 21999944
Highly Cited.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
K J Livak, T D Schmittgen.
Methods, 2002 Feb 16; 25(4). PMID: 11846609
Highly Cited.
Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain.
Dalei Wu, Nalini Potluri, Youngchang Kim, Fraydoon Rastinejad.
Mol Cell Biol, 2013 Sep 05; 33(21). PMID: 24001774    Free PMC article.
Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo.
João H Duarte, Paola Di Meglio, +2 authors, Brigitta Stockinger.
PLoS One, 2013 Nov 19; 8(11). PMID: 24244565    Free PMC article.
Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development.
J V Schmidt, G H Su, +2 authors, C A Bradfield.
Proc Natl Acad Sci U S A, 1996 Jun 25; 93(13). PMID: 8692887    Free PMC article.
Highly Cited.
Oral tolerance.
Howard L Weiner, Andre Pires da Cunha, Francisco Quintana, Henry Wu.
Immunol Rev, 2011 Apr 15; 241(1). PMID: 21488901    Free PMC article.
Highly Cited. Review.
Spontaneously relapsing-remitting experimental autoimmune uveitis in rats allows successful therapeutic oral tolerance induction in ongoing disease.
Andrea Huber, Maria Diedrichs-Möhring, Gerhild Wildner.
Mol Immunol, 2014 Aug 03; 63(2). PMID: 25085538
Oral tolerance to food protein.
O Pabst, A M Mowat.
Mucosal Immunol, 2012 Feb 10; 5(3). PMID: 22318493    Free PMC article.
Highly Cited. Review.
Oral tolerance: a biologically relevant pathway to generate peripheral tolerance against external and self antigens.
A Friedman, A al-Sabbagh, +5 authors, H L Weiner.
Chem Immunol, 1994 Jan 01; 58. PMID: 8011155
The in vivo and in vitro induction of anterior chamber associated immune deviation to myelin antigens in C57BL/6 mice.
Shukkur M Farooq, Walid F Elkhatib, Hossam M Ashour.
Brain Behav Immun, 2014 Jun 24; 42. PMID: 24953428
Regulation by intestinal γδ T cells during establishment of food allergic sensitization in mice.
M Bol-Schoenmakers, M Marcondes Rezende, +6 authors, J J Smit.
Allergy, 2010 Oct 01; 66(3). PMID: 20880210
Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding.
S Husby, J Mestecky, +2 authors, C O Elson.
J Immunol, 1994 May 01; 152(9). PMID: 8157979
The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology.
Charlotte Esser, Agneta Rannug.
Pharmacol Rev, 2015 Feb 07; 67(2). PMID: 25657351
Highly Cited. Review.
Oral tolerance.
Ana M C Faria, Howard L Weiner.
Immunol Rev, 2005 Jul 29; 206. PMID: 16048553    Free PMC article.
Highly Cited. Review.
Aryl hydrocarbon receptor controls regulatory CD4+ T cell function.
Caroline Pot.
Swiss Med Wkly, 2012 Jun 02; 142. PMID: 22653785
Prevalence of common food allergies in Europe: a systematic review and meta-analysis.
B I Nwaru, L Hickstein, +4 authors, EAACI Food Allergy and Anaphylaxis Guidelines Group.
Allergy, 2014 May 13; 69(8). PMID: 24816523
Highly Cited. Systematic Review.
A review of mechanisms underlying anticarcinogenicity by brassica vegetables.
D T Verhoeven, H Verhagen, +2 authors, G van Poppel.
Chem Biol Interact, 1997 Feb 28; 103(2). PMID: 9055870
The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells.
Elizabeth A Stanford, Zhongyan Wang, +7 authors, David H Sherr.
BMC Biol, 2016 Mar 18; 14. PMID: 26984638    Free PMC article.
Oral tolerance for treating uveitis - new hope for an old immunological mechanism.
Stephan R Thurau, Gerhild Wildner.
Prog Retin Eye Res, 2002 Nov 16; 21(6). PMID: 12433378
Activation of the aryl hydrocarbon receptor suppresses sensitization in a mouse peanut allergy model.
V J Schulz, J J Smit, +7 authors, R H H Pieters.
Toxicol Sci, 2011 Aug 02; 123(2). PMID: 21804081
A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.
Janine L Coombes, Karima R R Siddiqui, +4 authors, Fiona Powrie.
J Exp Med, 2007 Jul 11; 204(8). PMID: 17620361    Free PMC article.
Highly Cited.
Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
L F Bjeldanes, J Y Kim, +2 authors, C A Bradfield.
Proc Natl Acad Sci U S A, 1991 Nov 01; 88(21). PMID: 1658785    Free PMC article.
Highly Cited.
Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles.
Elina A Kiss, Cedric Vonarbourg, +4 authors, Andreas Diefenbach.
Science, 2011 Oct 29; 334(6062). PMID: 22033518
Highly Cited.
Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA.
Narendra P Singh, Udai P Singh, +4 authors, Mitzi Nagarkatti.
J Immunol, 2015 Dec 30; 196(3). PMID: 26712945    Free PMC article.
Oral tolerance: therapeutic implications for autoimmune diseases.
Ana M C Faria, Howard L Weiner.
Clin Dev Immunol, 2006 Dec 13; 13(2-4). PMID: 17162357    Free PMC article.
CD4(+) CD25(+) T regulatory cells do not transfer oral tolerance to peanut allergens in a mouse model of peanut allergy.
M Marcondes Rezende, I Hassing, +4 authors, R Pieters.
Clin Exp Allergy, 2011 Feb 23; 41(9). PMID: 21338425
3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103(+) Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5.
Joo-Hung Park, Ah-Jeong Choi, Soo-Ji Kim, So-Yeon Jeong.
Immune Netw, 2016 Jan 16; 15(6). PMID: 26770182    Free PMC article.
The aryl hydrocarbon receptor (AhR) ligand VAF347 selectively acts on monocytes and naïve CD4(+) Th cells to promote the development of IL-22-secreting Th cells.
Nobuyasu Baba, Manuel Rubio, +4 authors, Marika Sarfati.
Hum Immunol, 2012 May 23; 73(8). PMID: 22609446
Oral tolerance: is it all retinoic acid?
Harald von Boehmer.
J Exp Med, 2007 Jul 11; 204(8). PMID: 17620364    Free PMC article.
Modulation of systemic antigen-specific immune responses by oral antigen in humans.
Kerstin Kapp, Jochen Maul, +7 authors, Rainer Duchmann.
Eur J Immunol, 2010 Oct 20; 40(11). PMID: 20957752
Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy.
Palash Bhattacharya, Isadore Budnick, +5 authors, Bellur S Prabhakar.
J Interferon Cytokine Res, 2015 Mar 25; 35(8). PMID: 25803788    Free PMC article.
Highly Cited. Review.
Amelioration of Clostridium difficile Infection in Mice by Dietary Supplementation With Indole-3-carbinol.
Walker Julliard, Travis J De Wolfe, +3 authors, Joshua D Mezrich.
Ann Surg, 2016 Jun 10; 265(6). PMID: 27280500    Free PMC article.
Comparative analysis of homology models of the AH receptor ligand binding domain: verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor.
Domenico Fraccalvieri, Anatoly A Soshilov, +5 authors, Michael S Denison.
Biochemistry, 2013 Jan 05; 52(4). PMID: 23286227    Free PMC article.
A toolbox of novel murine house-keeping genes identified by meta-analysis of large scale gene expression profiles.
Markus Frericks, Charlotte Esser.
Biochim Biophys Acta, 2008 Sep 16; 1779(12). PMID: 18790095
Health benefits and possible risks of broccoli - an overview.
Klaus Peter Latté, Klaus-Erich Appel, Alfonso Lampen.
Food Chem Toxicol, 2011 Sep 13; 49(12). PMID: 21906651
Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor.
Michael S Denison, Anatoly A Soshilov, +2 authors, Bin Zhao.
Toxicol Sci, 2011 Sep 13; 124(1). PMID: 21908767    Free PMC article.
Highly Cited. Review.
Metabolism of vitamin A and its active metabolite all-trans-retinoic acid in small intestinal enterocytes.
A Lampen, S Meyer, T Arnhold, H Nau.
J Pharmacol Exp Ther, 2000 Nov 18; 295(3). PMID: 11082432
2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in mice.
Stefanie Chmill, Stephanie Kadow, +2 authors, Charlotte Esser.
Toxicol Sci, 2010 Aug 24; 118(1). PMID: 20729464
Retinoic acid imprints gut-homing specificity on T cells.
Makoto Iwata, Asami Hirakiyama, +3 authors, Si-Young Song.
Immunity, 2004 Oct 16; 21(4). PMID: 15485630
Highly Cited.
Experience-driven development: effector/memory-like alphaE+Foxp3+ regulatory T cells originate from both naive T cells and naturally occurring naive-like regulatory T cells.
Christiane Siewert, Uta Lauer, +4 authors, Jochen Huehn.
J Immunol, 2007 Dec 22; 180(1). PMID: 18097014
Induction of anergy or active suppression following oral tolerance is determined by antigen dosage.
A Friedman, H L Weiner.
Proc Natl Acad Sci U S A, 1994 Jul 05; 91(14). PMID: 8022835    Free PMC article.
Highly Cited.
DHA-rich tuna oil effectively suppresses allergic symptoms in mice allergic to whey or peanut.
Lieke W J van den Elsen, Marianne Bol-Schoenmakers, +6 authors, Linette E M Willemsen.
J Nutr, 2014 Oct 25; 144(12). PMID: 25342698
Optimization of murine small intestine leukocyte isolation for global immune phenotype analysis.
Andrew W Goodyear, Ajay Kumar, Steven Dow, Elizabeth P Ryan.
J Immunol Methods, 2014 Feb 11; 405. PMID: 24508527
Activation of the aryl hydrocarbon receptor AhR Promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4.
Rodica P Bunaciu, Andrew Yen.
Cancer Res, 2011 Jan 26; 71(6). PMID: 21262915    Free PMC article.
Eye-mediated immune tolerance to Type II collagen in arthritis-prone strains of mice.
Shukkur M Farooq, Ashok Kumar, Hossam M Ashour.
J Cell Mol Med, 2014 Sep 12; 18(12). PMID: 25211510    Free PMC article.
The search for endogenous activators of the aryl hydrocarbon receptor.
Linh P Nguyen, Christopher A Bradfield.
Chem Res Toxicol, 2007 Dec 14; 21(1). PMID: 18076143    Free PMC article.
Highly Cited. Review.
Dendritic cells in intestinal immune regulation.
Janine L Coombes, Fiona Powrie.
Nat Rev Immunol, 2008 May 27; 8(6). PMID: 18500229    Free PMC article.
Highly Cited. Review.
How vitamin A metabolizing dendritic cells are generated in the gut mucosa.
William W Agace, Emma K Persson.
Trends Immunol, 2011 Nov 15; 33(1). PMID: 22079120
Indole-3-Carbinol Promotes Goblet-Cell Differentiation Regulating Wnt and Notch Signaling Pathways AhR-Dependently.
Joo-Hung Park, Jeong-Min Lee, +2 authors, Da-Jeong Kim.
Mol Cells, 2018 Mar 23; 41(4). PMID: 29562732    Free PMC article.
Current results on the biological and pharmacological activities of Indole-3-carbinol.
Jae Kwang Kim, Sang Un Park.
EXCLI J, 2018 May 11; 17. PMID: 29743856    Free PMC article.
Enteric Microbiota⁻Gut⁻Brain Axis from the Perspective of Nuclear Receptors.
Kalina Duszka, Walter Wahli.
Int J Mol Sci, 2018 Aug 01; 19(8). PMID: 30060580    Free PMC article.
Aryl Hydrocarbon Receptor Ligands Indoxyl 3-sulfate and Indole-3-carbinol Inhibit FMS-like Tyrosine Kinase 3 Ligand-induced Bone Marrow-derived plasmacytoid Dendritic Cell Differentiation.
Won-Bhin Hwang, Da-Jeong Kim, Gap-Soo Oh, Joo-Hung Park.
Immune Netw, 2018 Nov 08; 18(5). PMID: 30402330    Free PMC article.
Gut Microbiome as Target for Innovative Strategies Against Food Allergy.
Roberto Berni Canani, Lorella Paparo, +7 authors, Danilo Ercolini.
Front Immunol, 2019 Mar 05; 10. PMID: 30828329    Free PMC article.
The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases.
Mayur Choudhary, Goldis Malek.
Int J Mol Sci, 2020 Sep 20; 21(18). PMID: 32947781    Free PMC article.
Mechanisms by which gut microorganisms influence food sensitivities.
Alberto Caminero, Marlies Meisel, Bana Jabri, Elena F Verdu.
Nat Rev Gastroenterol Hepatol, 2018 Sep 15; 16(1). PMID: 30214038    Free PMC article.
Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice.
Fenja A Schuran, Christoph Lommetz, +10 authors, Antonella Carambia.
Cell Mol Gastroenterol Hepatol, 2020 Sep 16; 11(2). PMID: 32932016    Free PMC article.
Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice.
Heather M Kahalehili, Nolan K Newman, +5 authors, Allison K Ehrlich.
Front Immunol, 2021 Feb 09; 11. PMID: 33552063    Free PMC article.
Modulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor.
Alba De Juan, Elodie Segura.
Front Immunol, 2021 Jun 08; 12. PMID: 34093534    Free PMC article.
Arsenic: Various species with different effects on cytochrome P450 regulation in humans.
Mahmoud A El-Ghiaty, Ayman O S El-Kadi.
EXCLI J, 2021 Sep 14; 20. PMID: 34512225    Free PMC article.
Intestinal Epithelial Cell-Derived CD83 Contributes to Regulatory T-Cell Generation and Inhibition of Food Allergy.
Yong Yu, Qiao-Ruo Jin, +6 authors, Peng-Yuan Zheng.
J Innate Immun, 2021 Jun 29; 13(5). PMID: 34182560    Free PMC article.