Cargando…

Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate...

Descripción completa

Detalles Bibliográficos
Autores principales: Fang, Wen-Feng, Chen, Yu-Mu, Lin, Chiung-Yu, Huang, Hui-Lin, Yeh, Hua, Chang, Ya-Ting, Huang, Kuo-Tung, Lin, Meng-Chih
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763578/
https://www.ncbi.nlm.nih.gov/pubmed/29344006
http://dx.doi.org/10.1186/s12950-018-0179-6
_version_ 1783291908186963968
author Fang, Wen-Feng
Chen, Yu-Mu
Lin, Chiung-Yu
Huang, Hui-Lin
Yeh, Hua
Chang, Ya-Ting
Huang, Kuo-Tung
Lin, Meng-Chih
author_facet Fang, Wen-Feng
Chen, Yu-Mu
Lin, Chiung-Yu
Huang, Hui-Lin
Yeh, Hua
Chang, Ya-Ting
Huang, Kuo-Tung
Lin, Meng-Chih
author_sort Fang, Wen-Feng
collection PubMed
description BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation. RESULTS: Results revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression. CONCLUSION: HDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages.
format Online
Article
Text
id pubmed-5763578
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-57635782018-01-17 Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression Fang, Wen-Feng Chen, Yu-Mu Lin, Chiung-Yu Huang, Hui-Lin Yeh, Hua Chang, Ya-Ting Huang, Kuo-Tung Lin, Meng-Chih J Inflamm (Lond) Research BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation. RESULTS: Results revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression. CONCLUSION: HDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages. BioMed Central 2018-01-10 /pmc/articles/PMC5763578/ /pubmed/29344006 http://dx.doi.org/10.1186/s12950-018-0179-6 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Fang, Wen-Feng
Chen, Yu-Mu
Lin, Chiung-Yu
Huang, Hui-Lin
Yeh, Hua
Chang, Ya-Ting
Huang, Kuo-Tung
Lin, Meng-Chih
Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression
title Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression
title_full Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression
title_fullStr Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression
title_full_unstemmed Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression
title_short Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression
title_sort histone deacetylase 2 (hdac2) attenuates lipopolysaccharide (lps)-induced inflammation by regulating pai-1 expression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763578/
https://www.ncbi.nlm.nih.gov/pubmed/29344006
http://dx.doi.org/10.1186/s12950-018-0179-6
work_keys_str_mv AT fangwenfeng histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression
AT chenyumu histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression
AT linchiungyu histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression
AT huanghuilin histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression
AT yehhua histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression
AT changyating histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression
AT huangkuotung histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression
AT linmengchih histonedeacetylase2hdac2attenuateslipopolysaccharidelpsinducedinflammationbyregulatingpai1expression