3,3′-Diindolylmethane alleviates oxazolone-induced colitis through Th2/Th17 suppression and Treg induction

Huang, Zhen; Jiang, Yucui; Yang, Yang; Shao, Jiushu; Sun, Xulun; Chen, Jiangning; Dong, Lei; Zhang, Junfeng

doi:10.1016/j.molimm.2012.09.007

Cited by 63 publications

(46 citation statements)

References 43 publications

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“…Recent reports purport the effective use of DIM in murine models of arthritis and steatosis (Huang et al, 2013;Liu et al, 2014). In mouse models of LPS-induced acute liver failure and experimental autoimmune encephalomyelitis, we have displayed its ability to attenuate disease progression, alleviating liver damage and halting central nervous system Fig.…”

Section: Discussionmentioning

confidence: 97%

“…Indigoid compounds have been extensively studied for their anti-cancer properties (Ahmad et al, 2010;Banerjee et al, 2011). The immunosuppressive role for DIM has been studied in a number of inflammatory diseases, including experimental arthritis (Dong et al, 2010), colitis (Huang et al, 2013), and autoimmune encephalomyelitis (Rouse et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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3,3'-Diindolylmethane Ameliorates Staphylococcal Enterotoxin B-Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells

Elliott

Nagarkatti

2016

Journal of Pharmacology and Experimental Therapeutics

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3,39-Diindolylmethane (DIM), a natural indole found in cruciferous vegetables, has significant anti-cancer and anti-inflammatory properties. In this current study, we investigated the effects of DIM on acute lung injury (ALI) induced by exposure to staphylococcal enterotoxin B (SEB). We found that pretreatment of mice with DIM led to attenuation of SEB-induced inflammation in the lungs, vascular leak, and IFN-g secretion. Additionally, DIM could induce cell-cycle arrest and cell death in SEB-activated T cells in a concentration-dependent manner. Interestingly, microRNA (miRNA) microarray analysis uncovered an altered miRNA profile in lung-infiltrating mononuclear cells after DIM treatment of SEB-exposed mice. Moreover, computational analysis of miRNA gene targets and regulation networks indicated that DIM alters miRNA in the cell death and cell-cycle progression pathways. Specifically, DIM treatment significantly downregulated several miRNA and a correlative increase associated gene targets. Furthermore, overexpression and inhibition studies demonstrated that DIM-induced cell death, at least in part, used miR-222. Collectively, these studies demonstrate for the first time that DIM treatment attenuates SEB-induced ALI and may do so through the induction of microRNAs that promote apoptosis and cell-cycle arrest in SEB-activated T cells.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

3,3'-Diindolylmethane Ameliorates Staphylococcal Enterotoxin B-Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells

Elliott

Nagarkatti

2016

Journal of Pharmacology and Experimental Therapeutics

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“…Among morbidities associated with chronic smoke inhalation are acute respiratory infection and a high risk of low-birth weight and infant mortality due to maternal exposure (Smith, et al 2000). Indeed, exposure to AHR ligands can mediate adaptive immune suppression in part through induction of Treg cells, which may increase susceptibility to viral or bacterial infections (Huang, et al 2013;Bruhs, et al 2015;Yang, et al 2016). In addition, PAH exposure can mediate an increased time to pregnancy, reduced spermatogenesis, and increased apoptosis of oocytes (MacKenzie and Angevine 1981; Matikainen, et al 2001;Revel, et al 2001;Esakky and Moley 2016).…”

Section: Discussionmentioning

confidence: 99%

Divergent Ah Receptor Ligand Selectivity during Hominin Evolution

et al. 2016

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We have identified a fixed nonsynonymous sequence difference between humans (Val381; derived variant) and Neandertals (Ala381; ancestral variant) in the ligand-binding domain of the aryl hydrocarbon receptor (AHR) gene. In an exome sequence analysis of four Neandertal and Denisovan individuals compared with nine modern humans, there are only 90 total nucleotide sites genome-wide for which archaic hominins are fixed for the ancestral nonsynonymous variant and the modern humans are fixed for the derived variant. Of those sites, only 27, including Val381 in the AHR, also have no reported variability in the human dbSNP database, further suggesting that this highly conserved functional variant is a rare event. Functional analysis of the amino acid variant Ala381 within the AHR carried by Neandertals and nonhuman primates indicate enhanced polycyclic aromatic hydrocarbon (PAH) binding, DNA binding capacity, and AHR mediated transcriptional activity compared with the human AHR. Also relative to human AHR, the Neandertal AHR exhibited 150-1000 times greater sensitivity to induction of Cyp1a1 and Cyp1b1 expression by PAHs (e.g., benzo(a)pyrene). The resulting CYP1A1/CYP1B1 enzymes are responsible for PAH first pass metabolism, which can result in the generation of toxic intermediates and perhaps AHR-associated toxicities. In contrast, the human AHR retains the ancestral sensitivity observed in primates to nontoxic endogenous AHR ligands (e.g., indole, indoxyl sulfate). Our findings reveal that a functionally significant change in the AHR occurred uniquely in humans, relative to other primates, that would attenuate the response to many environmental pollutants, including chemicals present in smoke from fire use during cooking.

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“…Dietary I3C or its condensation products have displayed therapeutic activity in mouse models of multiple sclerosis and DSS-induced colitis (Huang et al, 2013;Rouse et al, 2013). Both murine disease models are characterized by the induction of harmful inflammatory states that were alleviated through the AHR-dependent promotion of antiinflammatory Treg differentiation.…”

Section: Dietary Exposure To Indole-3-carbinolmentioning

confidence: 99%

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

473

432

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligandmediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.

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3,3′-Diindolylmethane alleviates oxazolone-induced colitis through Th2/Th17 suppression and Treg induction

Cited by 63 publications

References 43 publications

3,3'-Diindolylmethane Ameliorates Staphylococcal Enterotoxin B-Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells

3,3'-Diindolylmethane Ameliorates Staphylococcal Enterotoxin B-Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells

Divergent Ah Receptor Ligand Selectivity during Hominin Evolution

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

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