Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.

https://www.zora.uzh.ch/id/eprint/50509/1/Nature_article_final.pdf

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

The environment, diet, microbiota and body’s metabolism shape complex biological processes in health and disease. However, our understanding of the molecular pathways involved in these processes is still limited. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that integrates environmental, dietary, microbial and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific and context-specific manner. In this Review, we summarize our current knowledge of AHR and the transcriptional programmes it controls in the immune system. Finally, we discuss the role of AHR in autoimmune and neoplastic diseases of the central nervous system, with a special focus on the gut immune system, the gut–brain axis and the therapeutic potential of targeting AHR in neurological disorders. By sensing environmental, dietary, microbial and metabolic cues, the ligand-activated transcription factor aryl hydrocarbon receptor controls complex transcriptional programmes that are relevant to autoimmune, neoplastic, metabolic and degenerative diseases.

The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease.

Regulation of the Immune Response by the Aryl Hydrocarbon Receptor

// Ulrike M. Litzenburger 1,2,* , Christiane A. Opitz 1,2,3,* , Felix Sahm 2,4,5 , Katharina J. Rauschenbach 1,2 , Saskia Trump 6 , Marcus Winter 6 , Martina Ott 1,2 , Katharina Ochs 1,2 , Christian Lutz 7 , Xiangdong Liu 8 , Natasa Anastasov 9 , Irina Lehmann 6 , Thomas Hofer 10 , Andreas von Deimling 4,5 , Wolfgang Wick 1,11 , and Michael Platten 1,2 1 Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg, Heidelberg, Germany; 2 Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 3 Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, 4 Department of Neuropathology, Institute of Pathology, University Hospital of Heidelberg, Germany; 5 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 6 Department for Environmental Immunology, Helmholtz Center for Environmental Research, Leipzig, Germany, 7 Heidelberg Pharma GmbH, Ladenburg, Germany; 8 Incyte Corporation, Experimental Station, Wilmington, Delaware, USA, 9 Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Germany; 10 Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 11 Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany * These authors contributed equally to this work Correspondence: Michael Platten, email: // Christiane Opitz, email: // Keywords : IDO, immunosuppression, autoactivation loop Received : January 13, 2014 Accepted : January 18, 2014 Published : January 20, 2014 Abstract Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR–IL-6–STAT3 signaling loop. Inhibition of the AHR–IL-6–STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients.

/pdf/constitutive-ido-expression-in-human-cancer-is-sustained-by-40v5vqr0cw.pdf

Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target

The dioxin/aryl hydrocarbon receptor (AhR) is a transcription factor, which has been attributed a role in human cancerogenesis, cell cycle progression and transforming growth factor-beta (TGF-beta) signaling. As TGF-beta is an important mediator of the malignant phenotype of human gliomas, we studied AhR expression and function in glioma cells. AhR was not only expressed in glioma cells in vitro, but was also detected in human gliomas in vivo by immunohistochemistry, with a predominantly nuclear staining in glioblastomas. The AhR agonist, 3-methylcholanthrene, induced AhR nuclear translocation and upregulated mRNA levels of the AhR target gene, cytochrome P450 1A1 (CYP1A1). Conversely, pharmacological inhibition of AhR using the novel AhR antagonist, CH-223191, or AhR gene silencing using small interfering RNA showed that constitutive AhR activity positively controls TGF-beta1, TGF-beta2 and latent TGF-beta-binding protein-1 protein levels in malignant glioma cells. Moreover, antagonism of AhR reduced clonogenic survival and invasiveness of glioma cells. In contrast, AhR regulates TGF-beta signaling negatively in non-neoplastic astrocytes. Thus, the pathogenesis of glioma formation may involve altered AhR regulation of the TGF-beta/Smad pathway, and AhR may represent a promising target for the treatment of human malignant gliomas and other diseases associated with pathological TGF-beta activity.

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

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Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells