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Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells

Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing...

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Autores principales: Fu, Wenxian, Farache, Julia, Clardy, Susan M, Hattori, Kimie, Mander, Palwinder, Lee, Kevin, Rioja, Inmaculada, Weissleder, Ralph, Prinjha, Rab K, Benoist, Christophe, Mathis, Diane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270084/
https://www.ncbi.nlm.nih.gov/pubmed/25407682
http://dx.doi.org/10.7554/eLife.04631
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author Fu, Wenxian
Farache, Julia
Clardy, Susan M
Hattori, Kimie
Mander, Palwinder
Lee, Kevin
Rioja, Inmaculada
Weissleder, Ralph
Prinjha, Rab K
Benoist, Christophe
Mathis, Diane
author_facet Fu, Wenxian
Farache, Julia
Clardy, Susan M
Hattori, Kimie
Mander, Palwinder
Lee, Kevin
Rioja, Inmaculada
Weissleder, Ralph
Prinjha, Rab K
Benoist, Christophe
Mathis, Diane
author_sort Fu, Wenxian
collection PubMed
description Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a ‘combination therapy’ currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration. DOI: http://dx.doi.org/10.7554/eLife.04631.001
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spelling pubmed-42700842015-01-29 Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells Fu, Wenxian Farache, Julia Clardy, Susan M Hattori, Kimie Mander, Palwinder Lee, Kevin Rioja, Inmaculada Weissleder, Ralph Prinjha, Rab K Benoist, Christophe Mathis, Diane eLife Immunology Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a ‘combination therapy’ currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration. DOI: http://dx.doi.org/10.7554/eLife.04631.001 eLife Sciences Publications, Ltd 2014-11-19 /pmc/articles/PMC4270084/ /pubmed/25407682 http://dx.doi.org/10.7554/eLife.04631 Text en Copyright © 2014, Fu et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology
Fu, Wenxian
Farache, Julia
Clardy, Susan M
Hattori, Kimie
Mander, Palwinder
Lee, Kevin
Rioja, Inmaculada
Weissleder, Ralph
Prinjha, Rab K
Benoist, Christophe
Mathis, Diane
Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
title Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
title_full Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
title_fullStr Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
title_full_unstemmed Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
title_short Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
title_sort epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270084/
https://www.ncbi.nlm.nih.gov/pubmed/25407682
http://dx.doi.org/10.7554/eLife.04631
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