An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis.

Center for Neurologic Diseases, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2010; 107(48):20768-73. DOI: 10.1073/pnas.1009201107
Source: PubMed

ABSTRACT The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) participates in the differentiation of FoxP3(+) T(reg), Tr1 cells, and IL-17-producing T cells (Th17). Most of our understanding on the role of AHR on the FoxP3(+) T(reg) compartment results from studies using the toxic synthetic chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin. Thus, the physiological relevance of AHR signaling on FoxP3(+) T(reg) in vivo is unclear. We studied mice that carry a GFP reporter in the endogenous foxp3 locus and a mutated AHR protein with reduced affinity for its ligands, and found that AHR signaling participates in the differentiation of FoxP3(+) T(reg) in vivo. Moreover, we found that treatment with the endogenous AHR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) given parenterally or orally induces FoxP3(+) T(reg) that suppress experimental autoimmune encephalomyelitis. ITE acts not only on T cells, but also directly on dendritic cells to induce tolerogenic dendritic cells that support FoxP3(+) T(reg) differentiation in a retinoic acid-dependent manner. Thus, our work demonstrates that the endogenous AHR ligand ITE promotes the induction of active immunologic tolerance by direct effects on dendritic and T cells, and identifies nontoxic endogenous AHR ligands as potential unique compounds for the treatment of autoimmune disorders.

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    ABSTRACT: Recent studies show that the aryl hydrocarbon receptor (AhR) is involved in immune responses. AhR is activated following interaction with its ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). In this study, we investigated the role of AhR activation by its endogenous ligands in the pathogenesis of ocular Behcet's disease (BD). The expression of AhR was significantly decreased in active BD patients as compared to inactive BD patients and normal controls. Both FICZ and ITE inhibited Th1 and Th17 polarization and induced the expression of IL-22 by PBMCs and by CD4(+)T cells in active BD patients and normal controls. Stimulation of purified CD4(+)T cells with FICZ or ITE caused a decreased expression of RORC, IL-17, IL-23R, and CCR6 and an increased phosphorylation of STAT3 and STAT5. The present study suggests that a decreased AhR expression is associated with disease activity in BD patients. The activation of AhR by either FICZ or ITE was able to inhibit Th1 and Th17 cell polarization. Further studies are needed to investigate whether modulation of AhR might be used in the treatment of BD.
    Mediators of Inflammation 01/2014; 2014:195094. · 3.88 Impact Factor
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    ABSTRACT: Trung Nguyen and Taisuke Nakahama have contributed equally to this work. Aryl hydrocarbon receptor (AHR) is thought to be a crucial factor in the regulation of immune responses. Many AHR-mediated immunoregulatory mechanisms have been discovered, and this knowledge may enhance our understanding of the molecular pathogenesis of autoimmune inflammatory syndromes such as collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental colitis. Recent findings have elucidated the critical link between AHR and indoleamine 2,3-dioxygenase (IDO) in the development of regulatory T cells and Th17 cells, which are key factors in a variety of human autoim-mune diseases. Induction of IDO and IDO-mediated tryptophan catabolism, together with its downstream products such as kynurenine, is an important immunoregulatory mecha-nism underlying immunosuppression, tolerance, and immunity. Recent studies revealed that induction of IDO depends on AHR expression. This review summarizes the most cur-rent findings regarding the functions of AHR and IDO in immune cells as they relate to the pathogenesis of autoimmune diseases in response to various stimuli. We also discuss the potential link between AHR and IDO/tryptophan metabolites, and the involvement of several novel related factors (such as microRNA) in the development of autoimmune dis-eases. These novel factors represent potential therapeutic targets for the treatment of autoimmune disorders. Aryl hydrocarbon receptor (AHR) is a ligand-activated member of the Per–Arnt–Sim (PAS) family of basic helix–loop–helix (HLH) transcription factors. AHR mediates cellular responses to toxins or its ligands, including TCDD, 6-formylindolo[3,2-b]carbazole (FICZ), kynurenine, and 2-(1 H-indole-3 -carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) (1–4). AHR forms an active complex in the cytoplasm with chaperone proteins such as heat shock protein 90 (HSP90), AHR-interacting protein (AIP), and p23 (5–7). Once bound to its ligands, the AHR complex translo-cates to the nucleus and binds AHR nuclear translocator (Arnt). The resultant AHR–Arnt heterodimers bind specific motifs, called dioxin-responsive elements (DREs), in the promoter region of tar-get genes. These targets, the so-called AHR battery genes, include CYP1A1, CYP1A2, CYP1B1, and other members of cytochrome P450 family (8–11). Several pathways are involved in the regula-tion of AHR, including proteasomal degradation of AHR, ligand metabolism by CYP1A1, and formation of the AHR–Arnt complex (12, 13). One of these pathways involves an inhibitory peptide. Mimura et al. isolated a cDNA clone that encode a polypeptide with high similarity to the sequence of the bHLH/PAS of AHR (14). This polypeptide can repress the transcriptional activity of AHR by competing with AHR for binding to Arnt and by binding to the enhancer sequence XRE, upstream of the AHRR gene; therefore, this peptide is designated AHR repressor or AHRR. Expression of AHRR is induced by the AHR/Arnt heterodimer through binding to XRE, resulting in feedback inhibition of AHR. In addition, sev-eral transcription factors can interact and regulate AHR signaling; these include STAT-1, STAT3, STAT5, Pai-2, Sp1, c-maf, and Bach2 in certain cell types (15–24). AHR is activated in many immune cell types, including T cells, B cells, NK cells, macrophages, and dendritic cells (DCs), as well as in epithelial cells, Langerhans cells, innate lymphoid cells, intraepithelial lymphocytes, and microglia (15, 16, 20, 21, 25–40). Depending on the presence of specific lig-ands, AHR activation may suppress or exacerbate experimental autoimmune diseases. For examples, TCDD and ITE can suppress experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), whereas FICZ exacerbates disease devel-opment (17, 41–43). Differences in the stability and structure of these ligands, as well as their affinity for AHR, should be taken into account when considering their mode of action in the activa-tion of AHR. In addition, AHR seems to be regulated by unraveled factors such as transcription factors, tryptophan metabolites, feed-back regulation of the cytokine network, and microRNA (miR). Below, we will discuss in detail the factors that may interact with AHR to modulate immune responses.
    Frontiers in immunology. 11/2014; 5.
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    ABSTRACT: IL-22 as a cytokine is described with opposing pro-inflammatory and anti-inflammatory functions. Cell regeneration, tissue remodelling and balance between commensal bacteria in the gut and host immune system are considered as anti-inflammatory features of IL-22, whereas production of IL-22 from Th17 cells links this cytokine to pro-inflammatory pathways. Th17 cells and group 3 innate lymphoid cells (ILC3) are two major producers of IL-22 and both cell types express ROR-ct and Aryl hydrocarbon receptor (AhR) transcription factors. Typically, the immune system cells are the main producers of IL-22. However, targets of this cytokine are mostly non-hematopoietic cells such as hepatocytes, keratinocytes, and epithelial cells of lung and intestine. Association of IL-22 with other cytokines or transcription factors in different cell types might explain its contrasting role in health and disease. In this review we discuss the regulation of IL-22 production by AhR- and IL-23-driven pathways. A clear understanding of the biology of IL-22 will provide new opportunities for its application to improve human health involving many debilitating conditions.
    Cytokine 01/2015; · 2.52 Impact Factor

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