Cargando…

SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity

Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates inflammation is NF-κB, the activity of which is modulated by post-translational modifications as well as by association with co-activator and co-repressor prote...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Hongying, Zhang, Wei, Pan, Heng, Feldser, Heidi G., Lainez, Elden, Miller, Christine, Leung, Stewart, Zhong, Zhong, Zhao, Huizhen, Sweitzer, Sharon, Considine, Thomas, Riera, Thomas, Suri, Vipin, White, Brian, Ellis, James L., Vlasuk, George P., Loh, Christine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460821/
https://www.ncbi.nlm.nih.gov/pubmed/23029496
http://dx.doi.org/10.1371/journal.pone.0046364
_version_ 1782244990307532800
author Yang, Hongying
Zhang, Wei
Pan, Heng
Feldser, Heidi G.
Lainez, Elden
Miller, Christine
Leung, Stewart
Zhong, Zhong
Zhao, Huizhen
Sweitzer, Sharon
Considine, Thomas
Riera, Thomas
Suri, Vipin
White, Brian
Ellis, James L.
Vlasuk, George P.
Loh, Christine
author_facet Yang, Hongying
Zhang, Wei
Pan, Heng
Feldser, Heidi G.
Lainez, Elden
Miller, Christine
Leung, Stewart
Zhong, Zhong
Zhao, Huizhen
Sweitzer, Sharon
Considine, Thomas
Riera, Thomas
Suri, Vipin
White, Brian
Ellis, James L.
Vlasuk, George P.
Loh, Christine
author_sort Yang, Hongying
collection PubMed
description Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates inflammation is NF-κB, the activity of which is modulated by post-translational modifications as well as by association with co-activator and co-repressor proteins. SIRT1, an NAD(+)-dependent protein deacetylase, has been shown to suppress NF-κB signaling through deacetylation of the p65 subunit of NF-κB resulting in the reduction of the inflammatory responses mediated by this transcription factor. The role of SIRT1 in the regulation of NF-κB provides the necessary validation for the development of pharmacological strategies for activating SIRT1 as an approach for the development of a new class of anti-inflammatory therapeutics. We report herein the development of a quantitative assay to assess compound effects on acetylated p65 protein in the cell. We demonstrate that small molecule activators of SIRT1 (STACs) enhance deacetylation of cellular p65 protein, which results in the suppression of TNFα-induced NF-κB transcriptional activation and reduction of LPS-stimulated TNFα secretion in a SIRT1-dependent manner. In an acute mouse model of LPS-induced inflammation, the STAC SRTCX1003 decreased the production of the proinflammatory cytokines TNFα and IL-12. Our studies indicate that increasing SIRT1-mediated NF-κB deacetylation using small molecule activating compounds is a novel approach to the development of a new class of therapeutic anti-inflammatory agents.
format Online
Article
Text
id pubmed-3460821
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-34608212012-10-01 SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity Yang, Hongying Zhang, Wei Pan, Heng Feldser, Heidi G. Lainez, Elden Miller, Christine Leung, Stewart Zhong, Zhong Zhao, Huizhen Sweitzer, Sharon Considine, Thomas Riera, Thomas Suri, Vipin White, Brian Ellis, James L. Vlasuk, George P. Loh, Christine PLoS One Research Article Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates inflammation is NF-κB, the activity of which is modulated by post-translational modifications as well as by association with co-activator and co-repressor proteins. SIRT1, an NAD(+)-dependent protein deacetylase, has been shown to suppress NF-κB signaling through deacetylation of the p65 subunit of NF-κB resulting in the reduction of the inflammatory responses mediated by this transcription factor. The role of SIRT1 in the regulation of NF-κB provides the necessary validation for the development of pharmacological strategies for activating SIRT1 as an approach for the development of a new class of anti-inflammatory therapeutics. We report herein the development of a quantitative assay to assess compound effects on acetylated p65 protein in the cell. We demonstrate that small molecule activators of SIRT1 (STACs) enhance deacetylation of cellular p65 protein, which results in the suppression of TNFα-induced NF-κB transcriptional activation and reduction of LPS-stimulated TNFα secretion in a SIRT1-dependent manner. In an acute mouse model of LPS-induced inflammation, the STAC SRTCX1003 decreased the production of the proinflammatory cytokines TNFα and IL-12. Our studies indicate that increasing SIRT1-mediated NF-κB deacetylation using small molecule activating compounds is a novel approach to the development of a new class of therapeutic anti-inflammatory agents. Public Library of Science 2012-09-28 /pmc/articles/PMC3460821/ /pubmed/23029496 http://dx.doi.org/10.1371/journal.pone.0046364 Text en © 2012 Yang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Yang, Hongying
Zhang, Wei
Pan, Heng
Feldser, Heidi G.
Lainez, Elden
Miller, Christine
Leung, Stewart
Zhong, Zhong
Zhao, Huizhen
Sweitzer, Sharon
Considine, Thomas
Riera, Thomas
Suri, Vipin
White, Brian
Ellis, James L.
Vlasuk, George P.
Loh, Christine
SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity
title SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity
title_full SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity
title_fullStr SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity
title_full_unstemmed SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity
title_short SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity
title_sort sirt1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of nf-κb activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460821/
https://www.ncbi.nlm.nih.gov/pubmed/23029496
http://dx.doi.org/10.1371/journal.pone.0046364
work_keys_str_mv AT yanghongying sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT zhangwei sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT panheng sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT feldserheidig sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT lainezelden sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT millerchristine sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT leungstewart sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT zhongzhong sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT zhaohuizhen sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT sweitzersharon sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT considinethomas sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT rierathomas sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT surivipin sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT whitebrian sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT ellisjamesl sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT vlasukgeorgep sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity
AT lohchristine sirt1activatorssuppressinflammatoryresponsesthroughpromotionofp65deacetylationandinhibitionofnfkbactivity