Document Detail

Histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates Toll-like receptor 4 signaling in lipopolysaccharide-stimulated mouse macrophages.
MedLine Citation:
PMID:  22868051     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: We have previously demonstrated that pretreatment and posttreatment of animals with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can improve survival in a mouse model of lipopolysaccharide (LPS)-induced severe shock. This study was designed to assess whether SAHA affects LPS/Toll-like receptor 4 signaling through acetylation of heat shock protein 90 (HSP90) and degradation of its client protein interleukin-1 receptor-associated kinase 1 (IRAK1).
METHODS: RAW264.7 cells were exposed to LPS (1 μg/mL) for 2 h, followed by treatment with SAHA (10 μM) or geldanamycin (3 μM), an inhibitor of HSP90. Sham (no SAHA, no LPS) macrophages served as a control. The cells were harvested at different time points, and time zero served as the reference point.
RESULTS: LPS dramatically increased protein expression of myeloid differentiation factor 88 and IRAK1, and stimulated nuclear translocation of nuclear factor κB, leading to an increases of gene expression and protein production of tumor necrosis factor α and interleukin-6. Treatment with SAHA significantly attenuated these LPS-stimulated alterations. LPS or SAHA did not change the levels of HSP90 protein, but immunoprecipitation studies demonstrated that SAHA treatment enhanced acetylation of HSP90, and increased the dissociation of IRAK1, compared to the LPS control.
CONCLUSIONS: SAHA suppresses LPS/Toll-like receptor 4 signaling in LPS-stimulated macrophages through multiple potential mechanisms. It inhibits the function of HSP90 through hyperacetylation of the chaperone protein, which results in dissociation and degradation of the client protein IRAK1 and, at least in part, leads to a decrease in nuclear translocation of nuclear factor κB and attenuation of key proinflammatory cytokine expression.
Wei Chong; Yongqing Li; Baoling Liu; Ting Zhao; Eugene Y Fukudome; Zhengcai Liu; William M Smith; George C Velmahos; Marc A deMoya; Hasan B Alam
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-26
Journal Detail:
Title:  The Journal of surgical research     Volume:  178     ISSN:  1095-8673     ISO Abbreviation:  J. Surg. Res.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-02-25     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  0376340     Medline TA:  J Surg Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  851-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Active Transport, Cell Nucleus
Cells, Cultured
HSP90 Heat-Shock Proteins / analysis
Histone Deacetylase Inhibitors / pharmacology*
Hydroxamic Acids / pharmacology*
Interleukin-1 Receptor-Associated Kinases / analysis
Interleukin-6 / analysis,  genetics
Lipopolysaccharides / pharmacology*
Macrophages / drug effects*,  metabolism
Myeloid Differentiation Factor 88 / analysis
NF-kappa B / metabolism
Signal Transduction / drug effects*
Toll-Like Receptor 4 / physiology*
Tumor Necrosis Factor-alpha / analysis,  genetics
Grant Support
Reg. No./Substance:
0/HSP90 Heat-Shock Proteins; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Interleukin-6; 0/Lipopolysaccharides; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/NF-kappa B; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 4; 0/Tumor Necrosis Factor-alpha; 149647-78-9/vorinostat; EC Receptor-Associated Kinases; EC protein, mouse
Comment In:
J Surg Res. 2013 Nov;185(1):e35-6   [PMID:  23073512 ]

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