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The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells
The catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is a key step in tolerance effected by a variety of cell types, including mesenchymal stromal cells (MSCs). Trp catabolism generates molecules known as kynurenines, whose tolerance mechanisms involve activation of the Aryl Hydro...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696151/ https://www.ncbi.nlm.nih.gov/pubmed/29190885 http://dx.doi.org/10.18632/oncotarget.20166 |
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author | Lewis, Holly C. Chinnadurai, Raghavan Bosinger, Steven E. Galipeau, Jacques |
author_facet | Lewis, Holly C. Chinnadurai, Raghavan Bosinger, Steven E. Galipeau, Jacques |
author_sort | Lewis, Holly C. |
collection | PubMed |
description | The catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is a key step in tolerance effected by a variety of cell types, including mesenchymal stromal cells (MSCs). Trp catabolism generates molecules known as kynurenines, whose tolerance mechanisms involve activation of the Aryl Hydrocarbon Receptor (AHR). A synthetic analog of Trp, 1-methyl tryptophan (1MT), is a selective inhibitor of IDO enzymatic activity being utilized in cancer immunotherapy trials. We hypothesized 1MT might activate AHR independently of its effects on IDO. We demonstrate MSCs express AHR protein, and that in vitro treatment with 1MT causes AHR nucleotranslocation. Upon analyzing mRNA, we observed transcriptional upregulation of cytochrome p450 1a1 and 1b1 by 1MT racemic mixture (R-MT), consistent with AHR-activation. RNA-sequencing identified Nrf2, MAPK12 and IL-1a as downstream targets of 1MT. We demonstrate 1a1 and 1b1 activation by 1MT in IDO+ MSC following interferon-γ (IFN-γ) activation, suggesting AHR signaling is uncoupled from IDO catalytic function. Such a mechanism of action for 1MT may extend its usage to a wider range of patients, irrespective of tumor IDO expression. These observations support a novel paradigm by which AHR-activating compounds like 1MT can be used in cancer immunotherapy to stimulate a pro-inflammatory response. |
format | Online Article Text |
id | pubmed-5696151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56961512017-11-29 The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells Lewis, Holly C. Chinnadurai, Raghavan Bosinger, Steven E. Galipeau, Jacques Oncotarget Research Paper The catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is a key step in tolerance effected by a variety of cell types, including mesenchymal stromal cells (MSCs). Trp catabolism generates molecules known as kynurenines, whose tolerance mechanisms involve activation of the Aryl Hydrocarbon Receptor (AHR). A synthetic analog of Trp, 1-methyl tryptophan (1MT), is a selective inhibitor of IDO enzymatic activity being utilized in cancer immunotherapy trials. We hypothesized 1MT might activate AHR independently of its effects on IDO. We demonstrate MSCs express AHR protein, and that in vitro treatment with 1MT causes AHR nucleotranslocation. Upon analyzing mRNA, we observed transcriptional upregulation of cytochrome p450 1a1 and 1b1 by 1MT racemic mixture (R-MT), consistent with AHR-activation. RNA-sequencing identified Nrf2, MAPK12 and IL-1a as downstream targets of 1MT. We demonstrate 1a1 and 1b1 activation by 1MT in IDO+ MSC following interferon-γ (IFN-γ) activation, suggesting AHR signaling is uncoupled from IDO catalytic function. Such a mechanism of action for 1MT may extend its usage to a wider range of patients, irrespective of tumor IDO expression. These observations support a novel paradigm by which AHR-activating compounds like 1MT can be used in cancer immunotherapy to stimulate a pro-inflammatory response. Impact Journals LLC 2017-08-10 /pmc/articles/PMC5696151/ /pubmed/29190885 http://dx.doi.org/10.18632/oncotarget.20166 Text en Copyright: © 2017 Lewis et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Lewis, Holly C. Chinnadurai, Raghavan Bosinger, Steven E. Galipeau, Jacques The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells |
title | The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells |
title_full | The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells |
title_fullStr | The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells |
title_full_unstemmed | The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells |
title_short | The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells |
title_sort | ido inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696151/ https://www.ncbi.nlm.nih.gov/pubmed/29190885 http://dx.doi.org/10.18632/oncotarget.20166 |
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